Benzimidazole compounds

ABSTRACT

An antidiabetic compound selected from those of formula (I): ##STR1## wherein A, B, C, D, n, R 1 , R 2 , R 3 , R 4 , X, Y and Z are as defined in the description. 
     Medicaments containing the same.

The present invention relates to new tricyclic benzimidazole compounds,a process for their preparation, and pharmaceutical compositionscontaining them.

Imidazo[1,2-a]benzimidazoles possessing antihypertensive properties andcentral nervous system-depressant properties are known (Khim Farm., Zh79, 13, (8) pp 57-62).

The Applicant has now discovered tricyclic benzimidazole compounds thatexhibit an antidiabetic activity and at the same time a significantplatelet anti-aggregation activity. The combination of antidiabetic andplatelet anti-aggregation activities in one and the same molecule is atpresent novel and is of particular interest therapeutically. It is knownby the person skilled in the art that, apart from the metabolic problemsassociated with diabetes, the prognosis of that disease is aggravated bya significant risk of vascular complications (Goodman and Gilman's--Thepharmacological basis of Therapeutics, 8th edition, p. 1471). Thosecomplications require substantial monitoring and separate treatment. Asa result of their platelet anti-aggregation activity, currently notknown in compounds having an antidiabetic activity, the compounds of theinvention, whilst treating the metabolic disorders causing diabetes,also have a preventative and curative effect on cardiovascular disordersthat are an inevitable consequence of that disease. Based on that alone,the compounds of the invention represent decisive progress in thetreatment of diabetes compared with all the antidiabetic agents known inthe art. Finally, it is important to point out that the compounds of thepresent invention do not have any effect on arterial pressure, contraryto what might be expected from the ₋₋ -phenylethylamine structure ofcertain compounds of the invention as well as from results of the priorart already mentioned.

The present invention relates more especially to compounds of thegeneral formula (I): ##STR2## wherein: either:

1.

n=0

A, B, C and D, which are the same or different, each representshydrogen, halogen, a lower alkyl group, a lower alkoxy group, a hydroxygroup, a trifluoromethyl group or a hydroxy-lower alkyl group,

Y and Z each represents hydrogen or together form a bond, and either:

1.A.

X and R₂ together form a bond and in that case:

1.A.1

R₁ represents a G₁ group,

G₁ represents the group ##STR3## in which m is an integer of from 1 to 6inclusive and R₅ and R₆, which are the same or different:

a/ each represents, independently of the other, hydrogen, a lower alkylgroup, an aryl-lower alkyl group or a substituted aryl-lower alkylgroup, and R₃ represents hydrogen, a lower alkyl group, a phenyl nucleussubstituted by a lower alkyl group, by a hydroxy or hydroxyalkyl groupor by from two to five groups selected from lower alkyl, lower alkoxy,halogen, trifluoromethyl, hydroxy and hydroxyalkyl, or R₃ represents anaphthyl nucleus, a substituted naphthyl nucleus, a heteroaryl group, asubstituted heteroaryl group, or a group G₁, G₁ being as definedhereinbefore,

b/ or R₅ and R₆ together with the nitrogen atom that carries them form amorpholine system, and R₃ represents hydrogen, a lower alkyl group, aphenyl nucleus substituted by a lower alkyl group, hydroxy, halogen,trifluoromethyl or by hydroxyalkyl, or by from two to five groupsselected from lower alkyl, lower alkoxy, halogen, trifluoromethyl,hydroxy and hydroxyalkyl, or R₃ represents a naphthyl nucleus, asubstituted naphthyl nucleus, a heteroaryl group, a substitutedheteroaryl group, or a group G₁, G₁ being as defined herein before,

c/ or R₅ and R₆ together with the nitrogen atom that carries them form apiperidine, pyrrolidine or piperazine system each of which is optionallysubstituted at the nitrogen atom in the 4-position by a lower alkylgroup, an aryl group, an aryl-lower alkyl group, a substituted arylgroup or a substituted aryl-lower alkyl group, and R₃ represents a loweralkyl group, a phenyl nucleus substituted by hydroxy, halogen,trifluoromethyl or by a hydroxyalkyl group or by from two to five groupsselected from lower alkyl, lower alkoxy, halogen, trifluoromethyl,hydroxy and hydroxyalkyl, or R₃ represents a naphthyl nucleus, asubstituted naphthyl nucleus, a heteroaryl group or a substitutedheteroaryl group;

or R₁ represents a group G₂, G₂ denoting a (CH₂)_(m) COR₇ group, or G₃,G₃ denoting a (CH₂)_(m) CHOHR₇ group, wherein m is as definedhereinbefore and R₇ represents an aryl group or a substituted arylgroup, and R₃ represents hydrogen, a lower alkyl group, a phenyl nucleussubstituted by hydroxy, a hydroxyalkyl group, a lower alkoxy group or bya lower alkyl group or by from two to five groups selected from loweralkyl, lower alkoxy, halogen, trifluoromethyl, hydroxy and hydroxyalkyl,or R₃ represents a naphthyl nucleus, a substituted naphthyl nucleus, aheteroaryl group, a substituted heteroaryl group, or a group G₁, G₁being as defined hereinbefore,

R₄ represents hydrogen, a group G₁ with G₁ being as definedhereinbefore, a group G₄, that is to say a group of the formula:

    --COO--G.sub.1

wherein G₁ is as defined hereinbefore, or a group G₅, that is to sayCOR₉, wherein R₉ represents an aryl group, a substituted aryl group, aheteroaryl group or a substituted heteroaryl group, with the exceptionof compounds in which R₄ represents hydrogen at the same time as R₁represents a group: ##STR4## wherein m=2 and R₅ and R₆ each representsan ethyl group whilst at the same time R₃ represents a lower alkyl groupor a naphthyl group,

1.A.2

X and R₂ together form a bond and R₁ represents a group G₆, that is tosay a group (CH₂)_(m) R₈, m being as defined hereinbefore and R₈representing a lower alkyl group, or representing phenyl or substitutedphenyl or naphthyl or substituted naphthyl, and R₃ represents a loweralkyl group, an aryl group, a substituted aryl group, a heteroarylgroup, a substituted heteroaryl group, hydrogen or a group G₁, G₁ beingas defined hereinbefore, and R₄ represents a group G₁, G₄ or G₅, G₁, G₄and G₅ being as defined hereinbefore, or

1.A.3

X and R₂ together form a bond and R₁ represents methyl, and R₃represents a lower alkyl group, an aryl group, a substituted aryl group,a heteroaryl group, a substituted heteroaryl group, hydrogen or a groupG₁, G₁ being as defined hereinbefore, and R₄ represents a group G₄, G₄being as defined hereinbefore, or a group G₇, G₇ denoting the groupCOR₁₀ wherein R₁₀ represents a naphthyl group, a substituted naphthylgroup, a substituted phenyl group, a heteroaryl group or a substitutedheteroaryl group,

or

1.B

X and R₁ together form a bond,

R₂ represents:

a group G₁, G₁ being as defined hereinbefore, and R₃ represents a loweralkyl group, a substituted phenyl group, a naphthyl group, a substitutednaphthyl group, a heteroaryl group, a substituted heteroaryl group or agroup G₁, G₁ being as defined hereinbefore, whilst R₄ represents ahydrogen atom or a group G₁, G₄ or G₅, G₄ and G₅ being as definedhereinbefore,

or represents a group G₂ or a group G₃, G₂ and G₃ being as definedhereinbefore, and R₃ represents a hydrogen atom, a lower alkyl group, anaryl group, a substituted aryl group, a heteroaryl group, a substitutedheteroaryl group or a group G₁, G₁ being as defined hereinbefore, whilstR₄ represents a hydrogen atom or a group G₁, G₄ or G₅, G₄ and G₅ beingas defined hereinbefore,

or

2.

n=1,

A, B, C and D, which are the same or different, each represents ahydrogen atom, a halogen atom, a lower alkyl group or a trifluoromethylgroup,

X and R₁ form a bond or X and R₂ form a bond, wherein at least one ofthose two bonds must be present in the molecule,

Y and Z each represents a hydrogen atom or together form a bond,

R₁ or R₂ --depending on whether X and R₂ or X and R₁ form abond--represents a methyl group or G₁ or G₂ or G₃ or G₆, G₁, G₂, G₃ andG₆ each being as defined hereinbefore,

R₃ represents, whatever the meanings of R₁ and R₂, hydrogen, a loweralkyl group, an aryl group, a substituted aryl group, a heteroarylgroup, a substituted heteroaryl group or a group G₁, G₁ being as definedhereinbefore,

and R₄ represents a hydrogen atom or a group G₁ or G₄ or G₅, G₁, G₄ andG₅ being as defined hereinbefore, their stereoisomers, as well as theiraddition salts with a pharmaceutically acceptable acid, there beingunderstood by a lower alkyl or lower alkoxy group a straight-chain orbranched group containing from 1 to 6 carbon atoms, there beingunderstood by aryl group a phenyl or naphthyl group, and by heteroarylgroup a furyl, thienyl, pyridyl, pyrrolyl, imidazolyl, benzimidazolyl,benzofuryl, benzothienyl, quinolyl, isoquinolyl or indolyl group,

the term "substituted" qualifying the terms arylalkyl, aryl, phenyl,naphthyl and heteroaryl indicating, unless specified otherwise, that thegroups in question are substituted in the cyclic moiety by from one tothree radicals selected from halogen, trifluoromethyl, hydroxy, loweralkoxy, hydroxy-lower alkyl and lower alkyl, and that if there exists inone molecule several G₁ groups or R₅ and R₆ groups, those may be thesame or different.

Of the pharmaceutically acceptable acids that may be used to form anaddition salt of the compounds of formula (I) there may be mentioned byway of non-limiting example hydrochloric, sulfuric, tartaric, maleic,fumaric, oxalic, ethanesulfonic, camphonic, ethanesulfonic and citricacid etc.

The invention relates also to a process for the preparation of compoundsof the general formula (I) which is characterised in that:

A--when a compound of formula (I) is desired wherein X and R₂ togetherform a bond, there is used as starting material a compound of formula(II): ##STR5## wherein A, B, C, D and R₁ are as defined hereinbefore,the compound of formula (II) being obtained as described in theliterature (of which there may be cited by way of example and withoutimplying any limitation Tetrahedron 1976, 32(7), 839-842 or KhimHeterosikl, Soedin 1969(5), 869-873), which is treated:

* when a compound of formula (I) is desired wherein Y and Z eachrepresents a hydrogen atom, with a compound of formula (III/A):

    Hal.sub.A --(CH.sub.2).sub.n --CHR.sub.4 --CHR.sub.3 --P   (III/A)

wherein Hal_(A) represents halogen, n, R₃ and R₄ are as definedhereinbefore and P represents a leaving group selected from halogen andhydroxy, to yield a compound of formula (IV/A): ##STR6## wherein A, B,C, D and R₁ are as defined for formula (I) and n, R₃, R₄ and P are asdefined hereinbefore, which by means of heating, preceded, when Prepresents a hydroxy group, by treatment with a halogenation agent,yields a compound of formula (I/B): ##STR7## a particular case ofcompounds of formula (I) wherein A, B, C, D, R₁, R₃, R₄ and n are asdefined hereinbefore,

X and R₂ together forming a bond and Y and Z each representing ahydrogen atom,

* when a compound of formula (I) is desired wherein Y and Z togetherform a bond, with a compound of formula (III): ##STR8## wherein n is asdefined hereinbefore, R₃ is as defined for formula (I) as a function ofthe meanings of R₁, and Hal represents a halogen atom, to yield acompound of formula (IV): ##STR9## wherein Hal, A, B, C, D, R₁, n and R₃are as defined hereinbefore, which, by means of heating, yields acompound of formula (I/A): ##STR10## a particular case of compounds offormula (I) wherein A, B, C, D, R₁, R₃ and n are as definedhereinbefore, X and R₂ on the one hand, and Y and Z on the other hand,together form a bond, and R₄ represents hydrogen, which compound offormula (I/A), when a compound of formula (I) is desired in which R₄ isother than hydrogen, is treated:

- when a compound of formula (I) is desired wherein R₄ represents agroup G₄ and Y and Z represent a bond, with a compound of formula (V/A):

    Hal'.sub.3 --C--CO--Hal"                                   (V/A)

wherein Hal' and Hal", which are the same or different, each representshalogen, to yield a compound of formula (VI): ##STR11## wherein A, B, C,D, R₁, n, R₃ and Hal'₃ are as defined hereinbefore, which compound offormula (VI) is treated with a compound of formula VII: ##STR12##wherein m, R₅ and R₆ are as defined for the formula of group G₄ asdefined for formula (I), to yield a compound of formula (I/C): ##STR13##wherein A, B, C, D, R₁, R₃, R₅, R₆ and n are as defined for formula (I),

Y and Z on the one hand, and X and R₂ on the other hand, togetherforming a double bond, and R₄ representing a group G₄,

* when a compound of formula (I) is desired wherein R₄ represents agroup G₄ and Y and Z represent a bond, with a compound of formula(VIII):

    Hal"'--(CH.sub.2).sub.m --Hal.sub.4                        (VIII)

wherein Hal"' and Hal₄, which are the same or different, each representsa halogen atom and m is as defined hereinbefore, to yield a compound offormula (IX): ##STR14## wherein A, B, C, D, R₁, n, p, R₃ and Hal₄ are asdefined hereinbefore, which is then treated with a compound of formula(X): ##STR15## wherein R₅ and R₆ are as defined hereinbefore, to yield acompound of formula (I/D): ##STR16## a particular case of compounds offormula (I) wherein A, B, C, D, R₁ and n are as defined for formula (I),and X and R₂ on the one hand, and Y and Z on the other hand, togetherforming a bond, and R₄ forming a group G₁ as defined for formula (II),

* when a compound of formula (I) is desired wherein R₄ represents agroup G₅ or G₇ and Y and Z represent a bond, with a compound of formula(XI):

    Cl--CO--R.sub.9 ou Cl--CO--R.sub.10                        (XI)

depending on the compound desired, R₉ and R₁₀ being as definedhereinbefore, to yield a compound of formula (I/E): ##STR17## aparticular case of compounds of formula (I) wherein A, B, C, D, n and R₃are as defined hereinbefore, X and R₂ on the one hand, and Y and Z onthe other hand, together forming a bond, and R₄ representing a group G₅or G₇ as defined hereinbefore,

B.

when a compound of formula (I) is desired wherein X and R₁ together forma bond, there is used as starting material a compound of formula (XII):##STR18## wherein A, B, C, D and R₂ are as defined hereinbefore, which

* when a compound of formula (I) is desired wherein Y and Z eachrepresents hydrogen, is treated with a compound of formula (III/A) asdefined hereinbefore to yield, after heating, a compound of formula(I/G): ##STR19## a particular case of compounds of formula (I) whereinA, B, C, D, n, R₁, R₃ and R₄ are as defined hereinbefore, X and R₁together forming a bond and Y and Z each representing a hydrogen atom,

* when a compound of formula (I) is desired wherein Y and Z form a bond,is treated with a compound of formula (III) as defined hereinbefore, toyield, after heating, a compound of formula (I/F): ##STR20## aparticular case of compounds of formula (I) wherein A, B, C, D, n, R₂and R₃ are as defined hereinbefore,

X and R₁ on the one hand, and Y and Z on the other hand, togetherforming a bond, and R₄ representing hydrogen, which compound of formula(I/F), depending on the meaning of R₄ in the desired compound of formula(I), may be treated:

- in succession, as indicated hereinbefore, with a compound of formula(V/A) as defined hereinbefore then with a compound of formula (VII) asdefined hereinbefore,

- in succession, as indicated hereinbefore, with a compound of formula(VIII) as defined hereinbefore then with a compound of formula (X) asdefined hereinbefore,

- or with a compound of formula (XI) as defined hereinbefore, to yield acompound of formula (I/H): ##STR21## a particular case of compounds offormula (I) wherein A, B, C, D, n, R₂, R₃ and R₄ are as defined forformula (I), X and R₁ on the one hand, and Y and Z on the other hand,together forming a bond, which compounds of formulae (I), (I/A), (I/B),(I/C), (I/D), (I/E), (I/F), (I/G), (I/H) are, if necessary, purified bya technique selected from chromatography and/or crystallisation, and, ifdesired, convened with an acid into pharmaceutically acceptable salts.

The process for the synthesis of compounds of formula (I) indicatedabove is very general and may be subjected to any modifications that aperson skilled in the art might consider appropriate in order to carryout a synthesis specifically designed for any product of formula (I) hemight wish to obtain, this obviously being a function of the nature ofthe substituents A, B, C, D, R₁, R₂, R₃ and R₄. A certain number ofnon-limiting variants are described below.

One of the variants comprises subjecting to reduction with an alkalimetal mixed hydride a compound of formula (IV/B): ##STR22## obtained bycondensing a compound of formula (II) with a compound of formula(III/B): ##STR23## wherein Hal_(B) represents a halogen atom and n, R₃and R₄ are as defined hereinbefore to yield a compound of formula (IV/A)as defined hereinbefore in which the group P represents a hydroxy groupwhich compound, treated with a halogenation agent and then heated,yields a compound of formula (I/B) as defined hereinbefore.

Another variant relates to obtaining compounds of formula (I/B) asdefined hereinbefore in which R₁ represents a group G₂ or G₃, and Y andZ each represents hydrogen.

In that case, there is used as starting material a compound of formula(XIII): ##STR24## wherein A, B, C, D and n are as defined hereinbefore,which is treated with a halogenation agent and then by heating to yielda compound of formula (XIV): ##STR25## wherein A, B, C, D, R₃, R₄ and nare as defined hereinbefore, which is treated with a compound of formula(XV):

    Hal--(CH.sub.2).sub.m --CO--R.sub.7                        (XV)

wherein m and R₇ are as defined for formula (I) and Hal representshalogen, to yield a compound of formula (I/J): ##STR26## wherein A, B,C, D, m, n, R₃, R₄ and R₇ are as defined hereinbefore, Y and Z eachrepresenting a hydrogen atom, X and R₂ forming a bond, and R₁representing a group G₂, which compound of formula (I/J) may besubjected to the action of an alkali metal mixed hydride to yield acompound of formula (I/K): ##STR27## wherein A, B, C, D, m, n, R₃, R₄and R₇ are as defined hereinbefore, Y and Z each representing a hydrogenatom, X and R₂ together forming a bond, and R₁ representing a group G₃,which compounds of formulae (I/J) or (I/K) are, if necessary, purifiedand, if desired, converted into salts with a pharmaceutically acceptableacid.

Another means of obtaining compounds of formula (I/J) comprises treatingthe compound of formula (XIII) as defined hereinbefore with a compoundof formula (XV) as defined hereinbefore in order to obtain a compound offormula (XVI): ##STR28## wherein A, B, C, D, R₃, R₄, n, m and R₇ are asdefined hereinbefore, which is treated with a halogenation agent and byheating to yield a compound of formula (I/J) as defined hereinbefore.

Another means of obtaining a compound of formula (I/J) or (I/K)comprises using as starting material a compound of formula (XIV) (andnot a compound of formula XIII), which is treated as describedhereinbefore.

Another means of obtaining a compound of formula (I/K) comprisestreating the compound of formula (XIV) as defined hereinbefore with acompound of formula (XVII):

    Hal--(CH.sub.2).sub.m --CHOH--R.sub.7                      (XVII)

wherein Hal, m and R₇ are as defined for formula (I).

It is also possible to use as starting material compounds described inthe literature of the general formula: ##STR29## wherein A, B, C, D andR₁ are as defined hereinbefore, R represents a lower alkyl group orhydrogen and R' represents a lower alkyl group optionally substituted bya halogen atom or by a hydroxy group.

Such compounds are described in Khim. Farm., Zh, 1988, 22(7), 815-819 orin Khim. Geterotskl. Soedin., 1973(1), 111-114, or may be obtained bytreating a compound of formula (IV), as defined hereinbefore, wherein nis 0 and R₃ represents an OR group, with a compound of formula (XIX):##STR30## wherein P is a leaving group selected from halogen, hydroxyand lower (C₁ -C₆) alkoxy and R' is as defined hereinbefore, to yield,after heating, a compound of formula (XVIII). When R' represents amethyl group, the compounds (XVIII) are treated with N-bromosuccinimide,to yield a compound (XVIII') wherein R' represents a CH₂ Br group. WhenR' represents a lower alkyl group substituted by a hydroxy group,treatment with a halogenation agent allows a compound (XVIII") to beobtained wherein R' represents an alkyl group that is substituted by ahalogen atom.

Those compounds (XVIII) (when R' represents a lower alkyl groupsubstituted by a halogen), (XVllI') or (XVIII") may be treated with anamine of formula HNR₅ R₆ to yield, after heating in acidic medium, acompound of formula (I/L): ##STR31## wherein A, B, D, R₁, R₅ and R₆ areas defined for formula (I), a particular case of compounds of formula(I) wherein Y and Z on the one hand, and X and R_(l) on the other hand,together form a bond, R₄ represents a hydrogen atom, n is 0 and R₃represents a group K--NR₅ R₆ wherein K represents a lower alkylenegroup, which compound of formula (I/L) is, if desired, convened with anacid into a pharmaceutically acceptable salt.

More generally, the person skilled in the art could use this process,employing compounds of formula (XVIII) as starting material, to obtainother classes of compounds of formula (I) using customary chemicalreactions.

Another particular case concerns compounds in which R₄ represents agroup CH₂ NR₅ R₆. Those could be obtained by treating a compound offormula (I/A) as defined hereinbefore by means of a Mannich reactionusing formaldehyde and an amine HNR₅ R₆.

Another variant of the general process concerns the synthesis ofcompounds of formula (I) in which R₂ represents a group G₁.

Such compounds could be obtained by using as starting material acompound of formula (XX): ##STR32## wherein A, B, C, D and m are asdefined hereinbefore, which is treated with a compound of formula (XXI):

    Hal--(CH.sub.2).sub.n+1 --COR.sub.3                        (XXI)

wherein n and R₃ are as defined hereinbefore and Hal represents halogen,to yield a compound of formula (XXII): ##STR33## wherein A, B, C, D, R₃and m are as defined for formula (I) which, by means of heating, resultsin the formation of a compound of formula (XXIII): ##STR34## wherein A,B, C, D, m, n and R₃ are as defined for formula (I) which is treated:

a) with a halogenation agent,

b) with an amine of formula HNR₅ R₆, to enable a compound of formula(I/M) to be obtained: ##STR35## a particular case of compounds offormula (I) wherein A, B, C, D, m, n, R₃, R₅ and R₆ are as defined forformula (I),

R₁ and X, and Y and Z, in each case representing a bond and R₂representing a group G₁, which compound, if necessary, is purified and,if desired, is converted with an acid into a pharmaceutically acceptablesalt.

The compounds of formula (I) have valuable pharmacological properties.

Preliminary pharmacological studies have shown that the compounds of theinvention are non-toxic and simultaneously have a hypoglycaemic activityand a platelet anti-aggregration activity.

The compounds of the invention thus quite naturally are indicated fordiabetes and its cardiovascular complications (retinopathies, peripheraland cerebral vascular disorders).

The present invention also relates to pharmaceutical compositionscomprising as active ingredient at least one compound of the generalformula I or an addition salt thereof with a pharmaceutically acceptableacid, or, where appropriate, a pharmaceutically acceptable base, aloneor combined with one or more inert, non-toxic excipients or carriers.

Of the pharmaceutical compositions according to the invention there maybe mentioned more especially those that are suitable for oral,parenteral, nasal, rectal, percutaneous, transcutaneous, ophthalmic,respiratory or perlingual administration etc., and especially tablets,dragees, sublingual tablets, sachets, paquets, gelatin capsules,glossettes, pills, suppositories, creams, ointments, dermic gels,drinkable or injectable ampoules etc.

The dosage varies in accordance with the age and weight of the patient,the nature and severity of the disorder and also the route ofadministration. The latter may be oral, nasal, rectal or parenteral.

Generally, the unit dose ranges from 0.5 to 20 mg per administrationwith from one to four administrations in each 24 hours.

The following Examples illustrate the invention and do not limit it inany way.

The ¹ H nuclear magnetic resonance spectra were carried out using TMS(tetramethylsilane) as internal reference. The chemical shifts areexpressed in parts per million (ppm). The infrared spectra were cardedout by suspending the product in paraffin oil.

EXAMPLE 1 9-DIETHYLAMINOETHYL-2,3-DIHYDROIMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE ##STR36## STEP 1:2-Amino-1-diethylaminoethyl-3-(2-hydroxyethyl)benzimidazolehydrochloride

Heat at 130°-135° C. for approximately 40 minutes a mixture of (0.01mol) of 2-amino-1-[(2-diethylamino)ethyl]benzimidazole obtained asdescribed in J. Med. Chem. 72, 15 (9), 9236, and 3 ml of2-chloroethanol. After cooling, the reaction mixture is treated with amixture of ether/acetone until crystallisation occurs. Filter, and washthe residue with ether. Recrystallise from a mixture of alcohol/ether.

Yield: 90% Melting point: 159° C. Percentage composition: Calculated: C57.6 H 8.1 Cl 11.3 N 17.9 Found: C 57.4 H 8.0 Cl 11.0 N 17.8

STEP 2: 1-Diethylaminoethyl-2-imino-3-(2-chloroethyl)benzimidazoledihydrochloride

Heat at reflux 0.010 mol of the product obtained in Step 1 and 20 mol ofthionyl chloride that has previously been dissolved in 15 ml ofchloroform. Evaporate the resulting solution, and wash the residue withpetroleum ether to yield the title compound. Recrystallisation:ethanol-ether.

Yield: 100% Melting point: 214°-215° C. Percentage composition:Calculated: C 49.0 H 6.9 Cl 28.9 N 15.2 Found: C 49.2 H 6.7 Cl 28.5 N15.6

STEP 3: 9-Diethylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazoledihydrochloride

Add 10% ammonium hydroxide to 5 mmol of the product obtained in thepreceding Step and extract with chloroform; evaporate, add 10 ml ofo-xylene, and heat at reflux for one hour. After cooling, filter theprecipitate, wash it with petroleum ether, treat with a solution ofsodium carbonate and extract twice with chloroform (10 ml each time).The extract is eluted with chloroform on alumina gel. The eluate isevaporated, the residue is dissolved in acetone and the solution soobtained is treated with a solution of ethereal hydrogen chloride.Suction-filter the precipitate and wash with acetone and with ether.

Yield: 92% (hydrate crystals--1H₂ O) Melting point: 245°-246° C.(hydrate) (from ethanol) Percentage composition: Calculated: C 54.4 H7.3 Cl 21.4 N 16.9 Found: C 54.2 H 7.2 Cl 21.4 N 16.9 Spectralcharacteristics: Infrared: 1665 cm⁻¹ νC=N Nuclear magnetic resonance:(base) (CDCl₃) δ: 0.96 ppm, triplet, 6H, 2CH₃ δ: 6.82 ppm, unresolvedpeaks, 4H, aromatic.

EXAMPLE 2 9-MORPHOLINOETHYL-2,3-DIHYDROIMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE

The title compound is obtained by proceeding as in Example 1, but usingas starting material 2-amino-1-(2-morpholinoethyl)benzimidazole,obtained as described in Khim. Geterot sikl. Soedin; 69, (5), 869-873,instead of 2-amino-1-(2-diethylaminoethyl)benzimidazole.

Melting point: 282°-83° C. Percentage composition: Calculated: C 52.2 H6.4 Cl 20.5 N 16.2 Found: C 52.0 H 6.3 Cl 20.3 N 16.4

EXAMPLE 3 9-PHENACYL-2,3-DIHYDROIMIDAZO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE STEP A: 2-(2-Hydroxyethylamino)-1-phenacylbenzimidazoledihydrobromide

Heat at reflux for three hours 8.95 g (50 mmol) of2-(2-hydroxyethylamino)benzimidazole and 10 g of phenacyl bromide in 100ml of 2-propanol. Allow to cool. Suction-filter the resultingprecipitate and wash with acetone. The title compound is obtained.

Yield: 89% Melting point: 216°-217° C. (decomposition) Percentagecomposition: Calculated: C 54.3 H 4.8 Br 21.2 N 11.2 Found: C 54.1 H 5.0Br 21.0 N 11.2 Spectral characteristics: Infrared: 1702 cm⁻¹ νCO 1675cm⁻¹ νC=NH⁺.

STEP B: 2-(2-Hydroxyethylamino)-1-phenacylbenzimidazole (base)

Add 22% ammonium hydroxide to 75 ml of a hot solution of thedihydrobromide obtained in Step A in 95° alcohol until a pH ofapproximately 10 is obtained. The title compound precipitates and isfiltered, washed with water and dried.

Yield: 95% Melting point: 167°-168° C. (decomposition) Percentagecomposition: Calculated: C 69.2 H 5.8 N 14.2 Found: C 69.0 H 5.9 N 14.4Spectral characteristics: Infrared: 1525, 1580, 1615 cm⁻¹ νC=C and C=N1700 cm⁻¹ νC=O

STEP C: 1-Phenacyl-2-(2-chloroethylamino)benzimidazole hydrochloride

Add 0.7 ml (10 mmol) of freshly distilled thionyl chloride, withstirring, to a suspension of 1.5 g (5 mmol) of the base obtained abovein 25 ml of anhydrous chloroform. Heat the resulting solution at refluxfor 1 hour. After cooling, the 1-phenacyl-2-(2-chloroethylamino)benzimidazole hydrochloride precipitateis isolated by filtration, washed with petroleum ether andrecrystallised from a mixture of ethanol/ether.

Yield: 90% Melting point: 207°-208° C. (decomposition) Percentagecomposition: Calculated: C 58.3 H 4.9 Cl 20.2 N 12.0 Found: C 58.0 H 5.0Cl 19.9 N 12.3

STEP D: 2-(2-Chloroethylamino)-1-phenacylbenzimidazole

The hydrochloride obtained in Step C is treated with an aqueous ammoniumhydroxide solution, followed by extraction with chloroform of theresulting free base. Recrystallise the residue from benzene.

Yield: 87% Melting point: 115°-116° C. Spectral characteristics:Infrared: 1680 cm⁻¹ νCO 3300 cm⁻¹ νNH

STEP E: 9-Phenacyl-2,3-dihydroimidazo[1,2-a]benzimidazole

Heat 0.03 mol of 2-(2-chloroethylamino)-1-phenacylbenzimidazole to atemperature of 135°-140° C. obtained by an oil bath. After completemelting, the reaction mixture is crystallised. The reaction mixture isthen cooled and treated with 10 ml of a 22% strength aqueous ammoniumhydroxide solution and extracted three times with chloroform. Theorganic phases are combined and concentrated. The organic residue iseluted on a column of alumina and the eluate, after evaporation of thesolvent, forms the title compound.

Yield: 88% Melting point: 178°-179° C. Percentage composition:Calculated: C 73.3 H 5.4 N 15.2 Found: C 73.3 H 5.5 N 15.0 Spectralcharacteristics: Infrared: 1505, 1600 cm⁻¹ νC=C 1665 cm⁻¹ νC=N 1690 cm⁻¹νC=O Nuclear magnetic resonance: CDCl₃, δ=ppm δ=5.1; singlet, 2H, CH₂--CO δ=6.75, 7.54 and 7.9, three multiplets, 9H, aromatic.

STEP F: 9-Phenacyl-2,3-dihydroimidazo[1,2-a]benzimidazole hydrochloride

Dissolve 0.55 g of the base obtained in Step E in 20 ml of acetone, withthe application of heat, until a pH of 2-3 is obtained. Filter theresulting precipitate, wash with acetone and with ether andrecrystallise from alcohol.

Yield: 96% Melting point: 257°-258° C. (decomposition) Percentagecomposition: Calculated: C 65.1 H 5.1 Cl 11.3 N 13.4 Found: C 64.9 H 5.2Cl 11.0 N 13.1

EXAMPLE 4 9-PHENACYL-2,3-DIHYDROIMIDAZO[1,2-a]BENZIMIDAZOLE (secondsynthesising process)

Add 10 mmol (1.99 g) of phenacyl bromide to a hot solution of1H-2,3-dihydroimidazo [1,2-a]benzimidazole, described in J. Med. Chem.1982, 25(11), 1342-6, in 10 ml of 2-propanol. Heat at reflux for twohours. After cooling, the precipitate is collected by filtration andtreated with a 22% strength aqueous ammonium hydroxide solution to yieldthe title compound.

Yield: 95% Melting point: 178°-179° C.

That product may be treated in accordance with the protocol of Example3, Step F, to yield the hydrochloride.

EXAMPLE 5 9-(p-CHLOROPHENACYL)-2,3-DIHYDROIMIDAZO[1,2-a]BENZIMIDAZOLE,HYDROCHLORIDE

The title compound is obtained by proceeding as in Example 4 or as inExample 3, but replacing the phenacyl bromide (Example 3, Step A) with4'-chlorophenacyl bromide.

Melting point: 294°-295° C. Percentage composition: Calculated: C 58.7 H4.3 Cl 20.4 N 12.1 Found: C 58.7 H 4.4 Cl 19.9 N 12.3 Spectralcharacteristics: Infrared: 1500-1600 cm⁻¹ νCC 1660 cm⁻¹ νC=N 1695 cm⁻¹νC=O Nuclear magnetic resonance: CDCl₃ δ=ppm δ=5.02; singlet, 2H, CH₂--CO

EXAMPLE 6 9-(p-METHOXYPHENACYL)-2,3-DIHYDROIMIDAZO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE

The title compound is obtained by proceeding as in Example 4 or as inExample 3, but replacing the phenacyl bromide (Example 3, Step A) with4'-methoxyphenacyl bromide.

Melting point: 242°-243° C. Percentage composition: Calculated: C 62.9 H5.3 Cl 10.3 N 12.2 Found: C 62.7 H 5.2 Cl 10.0 N 12.4 Spectralcharacteristics: Infrared (base): 1500-1600 cm⁻¹ νC=C 1660 cm⁻¹ νC=N1695 cm⁻¹ νC=O Nuclear magnetic resonance: CDCl₃, (base) δ=3.75, 3H,singlet, OCH₃ δ=5.03, 2H, singlet, CH₂ O δ=6.75 and 7.90, 8H, 2multiplets, aromatic

EXAMPLE 7 9-(1-NAPHTHOYLMETHYL)-2,3-DIHYDROIMIDAZO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE

The title compound is obtained by proceeding as in Example 4 or as inExample 3, but replacing the phenacyl bromide (Example 3, Step A) withnaphthoylmethyl bromide.

Melting point: 202° C. (decomposition) Percentage composition:Calculated: C 64.7 H 5.7 Cl 11.2 N 13.3 Found: C 64.9 H 5.6 Cl 10.9 N13.4 Spectral characteristics: Infrared (base): 1665 cm⁻¹ νCN 2700-3055cm⁻¹ νOH

EXAMPLE 89-(2-HYDROXY-2-PHENYLETHYL)-2,3-DIHYDROIMIDAZO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE

Add bit by bit 0.3 g (7.5 mmol) of sodium borohydride to a suspension of1.94 g (7 mmol) of 9-phenacyl-2,3-dihydroimidazo[1,2-a]benzimidazole in15 ml of methanol over a period of thirty minutes at room temperature.Continue stirring for a further four hours and leave until the next day.Add 10 ml of 10% hydrochloric acid until a pH of 2-3 is obtained andevaporate the methanol. Treat the residue with a solution of ammoniumhydroxide and extract with chloroform. Recrystallise from ethanol theresidue from extraction.

Yield: 87% Melting point: 192° C. Percentage composition: Calculated: C73.0 H 6.7 N 15.0 Found: C 73.2 H 5.8 N 15.3 Spectral characteristics:Infrared (base): 1665 cm⁻¹ νC=N 2700-3055 cm⁻¹ νOH

The hydrochloride is obtained by adding ethereal hydrogen chloride to ahot ethanolic solution of the base obtained above (3 mmol, 0.84 g) untilan acidic mixture is obtained. Allow to cool, suction-filter and washwith ether.

Yield: (in relation to the base) 97.3% Melting point: 202° C. Percentagecomposition: Calculated: C 64.7 H 5.7 Cl 11.2 N 13.3 Found: C 64.9 H 5.6Cl 10.9 N 13.4 Spectral characteristics: Infrared (base): 1665 cm⁻¹ νC=N2700-3055 cm⁻¹ νOH

EXAMPLE 99-[2-HYDROXY-2-(4-CHLOROPHENYL)ETHYL]-2,3-DIHYDROIMIDAZO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE

The title compound is obtained by proceeding as in Example 8, butreplacing the 9-phenacyl-2,3-dihydroimidazo[1,2-a]benzimidazole with9-(p-chlorophenacyl)-2,3-dihydroimidazo [1,2-a]benzimidazole obtained inExample 5.

Melting point (hydrochloride): 208°-209° C. Percentage composition:Calculated: C 58.3 H 4.9 Cl 20.2 N 12.0 Found: C 58.4 H 4.7 Cl 20.5 N11.8 Spectral characteristics: Infrared (base): 1650 cm⁻¹ νC=N 2690-3060cm⁻¹ νOH

EXAMPLE 109-[2-(1-NAPHTHYL)-2-HYDROXYETHYL]-2,3-DIHYDROIMIDAZO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE

The title compound is obtained by proceeding as in Example 8, butreplacing the 9-phenacyl-2,3-dihydroimadazo[1,2-a]benzimidazole with9-(1-naphthoylmethyl)-2,3-dihydroimidazo [1,2-a]benzimidazole obtainedin Example 7.

Melting point: 214°-215° C. Percentage composition: Calculated: C 68.9 H5.5 Cl 9.7 N 11.5 Found: C 68.8 H 5.7 Cl 9.5 N 11.4 Spectralcharacteristics: Infrared (base): 1650 cm⁻¹ νC=N 2700-3055 cm⁻¹ νOH

EXAMPLE 11 9-DIETHYLAMINOETHYL-2-(4-TOLYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROBROMIDE STEP A:2-Amino-1-diethylaminoethyl-3-(4-toluoyl-methyl)benzimidazoliumhydrobromide

Add 2.13 g (10 mmol) of 4-methylphenacyl bromide to a hot solution of2.32 g of 2-amino-1-diethylaminoethyl benzimidazole in 50 ml of acetone.Stir the mixture carefully for one night at room temperature. The nextday, suction-filter the precipitate and wash with acetone.

Yield: 96% Melting point: 195°-196° C. Percentage composition:Calculated: C 59.3 H 6.6 Br 17.9 N 12.6 Found: C 59.3 H 6.5 Br 17.7 N12.8 Spectral characteristics: Infrared (base): 1690 cm⁻¹ νC=O 1670 cm⁻¹νCN 3150-3310 cm⁻¹ νNH₂

STEP B: 9-Diethylaminoethyl-2-(4-tolyl)-imidazo[1,2-a]benzimidazoledihydrobromide

The hydrobromide obtained in Step A is heated at the boil inconcentrated hydrobromic acid for 2 hours. Cool the reaction mixture andplace it in the refrigerator for one night. Suction-filter the titlecompound, wash with acetone and recrystallise from ethanol.

Melting point: 239° C. Percentage composition: Calculated: C 52.0 H 5.6Br 31.4 N 11.0 Found: C 52.2 H 5.5 Br 31.2 N 11.1 Spectralcharacteristics: Infrared (base): 1615, 1605, 1508 cm⁻¹ νC=C, νC=NNuclear magnetic resonance: ¹ H, (CDCl₃) δ=0.76 ppm, 6H, triplet, 2(CH₂CH₃) δ=2.18 ppm, 3H, singlet, C₆ H₄ --CH₃ δ=2.45 ppm, 4H, quadruplet,2(CH₂ --CH₃) δ=7.15-7.48 ppm, unresolved peaks, 9H, aromatic

N.B.: a second portion of hydrobromide (0.35 g) can be obtained byrendering alkaline the mother liquors followed by column chromatographyof the base and conversion of the latter into a salt.

EXAMPLE 122-TERT-BUTYL-9-(2-MORPHOLINOETHYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROBROMIDE STEP A:2-Amino-1-(2-morpholinoethyl)-3-pivaloylmethyl-benzimidazoliumhydrobromide

A hot solution of 2-amino-1-morpholinoethyl benzimidazole in 25 ml ofethanol is mixed with 1.35 g (10 mmol) of bromopinacolone, heated atreflux for 10 minutes, left at room temperature for 3 hours and dilutedtwice with acetone. The resulting precipitate is filtered and washedwith acetone to yield the title compound.

Yield: 87% Melting point: 195°-196° C. (decomposition) Percentagecomposition: Calculated: C 53.6 H 6.9 Br 18.8 N 13.2 Found: C 53.5 H 6.7Br 19.0 N 13.4 Spectral characteristics: Infrared (base): 1665 cm⁻¹ νC=N1715 cm⁻¹ νCO

STEP B: 2-Tert-butyl-9-morpholinoethylimidazo[1,2-a]benzimidazolehydrochloride

The hydrobromide obtained in Step A is heated at reflux in concentratedhydrochloric acid for 30 minutes. The solution is cooled and neutralisedwith an aqueous ammonium hydroxide solution. The reaction mixture isextracted with benzene and the extract is dried over sodium sulfate.Subsequently, pass through a stream of gaseous hydrochloric acid untilacidity. The resulting precipitate is filtered and recrystallised fromethanol.

Yield: 87% Melting point: 263°-264° C. Percentage composition:Calculated: C 57.1 H 7.1 Br 17.8 N 14.0 Found: C 57.0 H 6.9 Br 17.5 N14.2 Spectral characteristics: Infrared (base): 1505, 1600, 1620 cm⁻¹νC=C, νC=N

EXAMPLE 132-TERT-BUTYL-9-(2-MORPHOLINOETHYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEHYDROBROMIDE

The title compound is obtained by proceeding as in Example 12, butreplacing the stream of gaseous hydrochloric acid in Step B with astream of gaseous hydrobromic acid.

Melting point: 294°-295° C. Percentage composition: Calculated: C 46.7 H5.8 Br 32.4 N 11.5 Found: C 46.5 H 6.0 Br 32.4 N 11.6

EXAMPLE 142-TERT-BUTYL-9-(3-DIMETHYLAMINOPROPYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE STEP A:2-Amino-1-(3-dimethylaminopropyl)-3-pivaloyl-methylbenzimidazolium

React 10 mmol (2.18 g) of 2-amino-1-dimethylaminopropyl-benzimidazoleand 10 mmol (1.35 ml) of bromopinacoline in 70 ml of acetone.

Recrystallisation: ethanol/acetone/ether Yield: 90% Melting point:197°-198° C. (decomposition) Percentage composition: Calculated: C 54.4H 7.4 Br 20.1 N 14.1 Found: C 54.2 H 7.4 Br 19.8 N 14.1 Spectralcharacteristics: Infrared (base): 1720 cm⁻¹ νC=O 1660 cm⁻¹ νC=N 3050,3250 cm⁻¹ νNH

STEP B:2-Tert-butyl-9-(3-dimethylaminopropyl)-imidazo[1,2-a]benzimidazole

Heat at reflux for 25 minutes 3 mmol of the hydrobromide obtained inStep A and 4 g of sodium carbonate in 25 ml of ethanol. Evaporate, treatthe residue twice with 10 ml of chloroform each time, and pass theresulting chloroform solutions over a column of aluminia. Evaporate theeluate. The title compound is obtained in the form of an oil.

Yield: 90% Percentage composition: Calculated: C 72.4 H 8.8 N 18.8Found: C 72.2 H 8.7 N 18.9 Spectral characteristics: Infrared (base):1510, 1605, 1625 cm⁻¹ νC=C, νC=N

STEP C:2-Tert-butyl-9-(3-dimethylaminopropyl)-imidazo[1,2-a]benzimidazoledihydrochloride

Dissolve the oil obtained in Step B in 15 ml of anhydrous ether andacidify with ethereal hydrogen chloride. Filter the resultingprecipitate and purify by means of reprecipitation with ehter from anethanolic solution.

Yield: 92% Melting point: 258°-259° C. Percentage composition:Calculated: C 58.2 H 7.6 Cl 19.1 N 15.1 Found: C 57.9 H 7.8 Cl 18.8 N15.2

EXAMPLE 152-TERT-BUTYL-9-(3-DIMETHYLAMINOPROPYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIPERCHLORATE

The title compound is obtained by proceeding as in Example 14 butreplacing the hydrochloric acid in step C with perchloric acid.

Melting point: 236°-237° C. Percentage composition: Calculated: C 43.3 H5.7 Cl 14.2 N 11.2 Found: C 43.2 H 5.5 Cl 14.0 N 11.0

EXAMPLE 169-(2-MORPHOLINOETHYL)-2-(4-HYDROXYPHENYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIPERCHLORATE STEP A:9-(2-Morpholinoethyl)-2-(4-hydroxyphenyl)-imidazo[1,2-a]benzimidazole

A mixture of 2-amino-1-(2-morpholinoethyl)benzimidazole (10 mmol, 2.46g) and 4-hydroxyphenacyl bromide (10 mmol, 2.15 g) (obtained bybromination of parahydroxyacetophenone with cuptic bromide in a mixtureof chloroform and ethyl acetate) is heated at reflux for 1 hour in 10 mlof dimethylformamide. After cooling, the mixture is poured into 50 ml ofwater and rendered alkaline with ammonium hydroxide. The resulting oilis removed and treated with water. The crystallised residue is filtered,dried, and recrystallised from ethanol.

Yield: 52% Melting point: 228°-229° C. Percentage composition:Calculated: C 69.6 H 6.1 N 15.5 Found: C 69.5 H 6.2 N 15.5 Spectralcharacteristics: Infrared: 3350-3200 cm⁻¹ νOH 1500, 1600, 1605 cm⁻¹ νC=CνC=N Nuclear magnetic resonance: ¹ H, (CDCl₃) δ=2.48 ppm, triplet, 4H,N(CH₂)₂ morpholine δ=2.78 ppm, triplet, 2H, CH₂ -(morpholine) δ=3.56ppm, triplet, 4H, (CH₂)₂ O δ=4.26 ppm, triplet, 2H, N--CH₂ --CH₂-morpholine δ=6.85-7.45 ppm, multiplet, 9H, aromatic

STEP B:9-(2-Morpholinoethyl)-2-(4-hydroxyphenyl)-imidazo[1,2-a]benzimidazoledihydrochloride

Heat 5 mmol (1.81 g) of the base obtained in Step A in 10 ml of ethanoland acidify with a hydrochloric acid ispropanol solution. Cool, filter,wash with ethanol and with acetone and recrystallise from a mixture ofethanol and water.

Yield: 81% Melting point: 276°-277° C. Percentage composition:Calculated: C 57.9 H 5.6 Cl 16.3 N 12.9 Found: C 57.7 H 5.5 Cl 16.0 N12.8

That compound can also be obtained by using the procedure in Example 11but, in Step A, replacing:

-4-methylphenacyl bromide with 4-methoxyphenacyl bromide and

-2-amino-1-[(2-diethylamino)ethyl]benzimidazole with2-amino-1-[(2-morpholino)ethyl]benzimidazole.

The cyclisation reaction in the boiling hydrobromic acid is accompaniedby hydrolysis of the methoxy group, and in that manner the hydrobromideis obtained.

EXAMPLE 179-(2-MORPHOLINOETHYL)-2-(3-HYDROXYPHENYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROBROMIDE

The title compound is obtained by proceeding as in Example 11 but, inStep A, replacing:

-4-methylphenacyl bromide with 3-methoxyphenacyl bromide and

-2-amino-1-(2-diethylaminoethyl)benzimidazole with2-amino-1-(2-morpholinoethyl)benzimidazole.

Melting point: 275°-277° C. Percentage composition: Calculated: C 48.1 H4.6 Br 30.5 N 10.7 Found: C 48.2 H 4.5 Br 30.2 N 10.5

EXAMPLES 18 TO 24

By proceeding as in Example 11 , but using as starting materials:

- appropriately substituted benzimidazole compounds,

- appropriately substituted aroylmethyl halides, the following areobtained:

EXAMPLE 189-DIETHYLAMINOETHYL-2-(3,4-DIMETHOXYPHENYL)-IMIDAZO[1,2-a]BENZIMIDAZOLESULFATE

Melting point: 248°-249° C. (decomposition) Percentage composition:Calculated: C 56.3 H 6.2 N 11.4 S 6.5 Found: C 56.2 H 6.0 N 11.5 S 6.3Spectral characteristics: Infrared: 1510, 1600, 1610 cm⁻¹ (νC=C νC=N)Nuclear magnetic resonance: (CDCl₃) δ=0.92 ppm, triplet, 6H, 2(OCH₃)δ=2.54 ppm, quadruplet, 4H, 2(CH₂ --CH₃) δ=2.88 ppm, triplet, 2H, CH₂CH₂ N(Et)₂ δ=4.20 ppm, triplet, 2H, CH₂ CH₂ N(Et)₂

EXAMPLE 199-DIETHYLAMINOETHYL-2-(3,4-DIHYDROXYPHENYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDINITRATE

Melting point: 198°-199° C. (decomposition) Percentage composition:Calculated: C 51.4 H 5.3 N 17.1 Found: C 51.2 H 5.4 N 17.2 Spectralcharacteristics:

    ______________________________________                                        Infrared:                                                                              1510, 1590, 1605 cm.sup.-1                                                                    ν C═C                                                                            ν C═N                                        3200-3350 cm.sup.-1                                                                           ν OH                                              ______________________________________                                    

EXAMPLE 209-(2-DIETHYLAMINOETHYL)-2-(3,4-DIHYDROXYPHENYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE

Melting point: 276°-278° C. Percentage composition: Calculated: C 57.7 H6.0 Cl 16.2 N 12.8 Found: C 57.5 H 6.3 Cl 16.6 N 13.0 Spectralcharacteristics:

    ______________________________________                                        Infrared:                                                                              1510, 1590, 1605 cm.sup.-1                                                                    ν C═C                                                                            ν C═N                                        3200-3350 cm.sup.-1                                                                           ν OH                                              ______________________________________                                    

EXAMPLE 219-(2-PIPERIDINOETHYL)-2-(3,4-DIHYDROXYPHENYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROBROMIDE

Melting point: 297°-298° C. (decomposition) Percentage composition:Calculated: C 49.1 H 4.9 Br 29.7 N 10.4 Found: C 48.9 H 5.2 Br 29.5 N10.3

EXAMPLE 229-(2-PIPERIDINOETHYL)-2-(3,4-DIHYDROXYPHENYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDINITRATE

Melting point: 215°-216° C. Percentage composition: Calculated: C 52.6 H5.2 N 16.7 Found: C 52.4 H 5.2 N 16.7 Spectral characteristics:

    ______________________________________                                        Infrared (base):                                                                        1500, 1595, 1605 cm.sup.-1                                                                    ν C═C                                                                            ν C═N                                        3200-3600 cm.sup.-1                                                                           ν OH                                             ______________________________________                                    

EXAMPLE 239-(2-PIPERIDINOETHYL)-2-(3,4-DIHYDROXYPHENYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE

Melting point: 293°-294° C. Percentage composition: Calculated: C 58.8 H5.8 Cl 15.8 N 12.5 Found: C 58.6 H 5.8 Cl 15.7 N 12.7

EXAMPLE 249-(2-DIETHYLAMINOETHYL)-2-(1-METHYL-2-BENZIMIDAZOLYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROBROMIDE HYDRATE

Melting point: 280°-281° C. Percentage composition: Calculated: C 48.8 H5.3 Br 28.2 N 14.9 Found: C 48.6 H 5.5 Br 28.4 N 14.7

EXAMPLE 259-(2-DIETHYLAMINOETHYL)-2-(2-THIENYL))-IMIDAZO[1,2-a]BENZIMIDAZOLEDIPERCHLORATE

Melting point: 139°-140° C. Spectral characteristics: ¹ H NMR (CF₃ COOD)δ=1.00 ppm, 6H, triplet, 2CH₃ δ=3.14 ppm, 4H, quadruplet, 2 CH₂ --CH₃δ=3.49 ppm, 2H, triplet, CH₂ N--(CH₂ CH₃)₂ δ=4.60 ppm, 2H, triplet, CH₂CH₂ N(CH₂ CH₃)₂

EXAMPLE 269-(2-DIETHYLAMINOETHYL)-2-(2-THIENYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEPHOSPHATE

Melting point: 188°-189° C. Spectral characteristics: ¹ H NMR (CF₃ COOD)δ=1.10 ppm, 6H, triplet, 2CH₃ δ=3.18 ppm, 4H, quadruplet, 2 CH₂ --CH₃δ=3.53 ppm, 2H, triplet, CH₂ N--(CH₂ CH₃)₂ δ=4.70 ppm, 2H, triplet, CH₂CH₂ N(CH₂ CH₃)₂

EXAMPLE 279-(2-PIPERIDINOETHYL)-2-(2-THIENYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROBROMIDE

Melting point: 295.5°-296° C. (decomposition) Percentage composition:Calculated: C 46.9 H 4.7 Br 31.2 N 10.9 S 6.3 Found: C 47.0 H 4.9 Br30.9 N 10.9 S 6.3 Spectral characteristics:

    ______________________________________                                        Infrared (base):                                                                        1500, 1600, 1615 cm.sup.-1                                                                    ν C═C                                                                            ν C═N                                        3200-3600 cm.sup.-1                                                                           ν OH                                             ______________________________________                                    

EXAMPLE 289-(2-PIPERIDINOETHYL)-2-(2-THIENYL)-IMIDAZO[1,2-a]BENZIMIDAZOLE SULFATE

Melting point: 265°-266° C. (decomposition) Percentage composition:Calculated: C 53.5 H 5.4 N 12.5 S 14.3 Found: C 53.4 H 5.7 N 12.7 S 14.5

EXAMPLE 299-(2-PIPERIDINOETHYL)-2-(5-BROMO-2-THIENYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE STEP A:2-Amino-3-(5-bromo-2-thenoylmethyl)-1-(2-piperidinoethyl)-benzimidazolehydrobromide

Add a solution of 5-bromo-2-bromoacetylthiophene (5.68 g, 20 mmol) in 30ml of ether to a hot solution of2-amino-1-(2-piperidinoethyl)-benzimidazole (4.88 g, 20 mmol) in 150 mlof acetone. Stir and maintain at room temperature for five hours.Suction-filter the precipitate, wash with acetone and then with ether toobtain the title compound.

Yield: 82% Melting point: 185° C. (decomposition) Percentagecomposition: Calculated: C 45.4 H 4.6 Br 30.2 N 10.6 S 6.1 Found: C 45.3H 4.8 Br 30.6 N 10.7 S 6.5 Spectral characteristics:

    ______________________________________                                        Infrared (base):                                                                            1680 cm.sup.-1 ν C═N                                                   1695 cm.sup.-1 ν CO                                                        3120, 3315 cm.sup.-1                                                                         ν NH.sub.2                                    ______________________________________                                    

STEP B:9-(2-Piperidinoethyl)-2-(5-bromo-2-thienyl)-imidazo[1,2-a]benzimidazoledihydrochloride

The hydrobromide obtained in Step A is heated at melting for 20 minutesat 190° C. After cooling, the resulting product is treated with 10 ml ofammonium hydroxide and extracted with benzene. The organic phases arecombined, concentrated and passed over a column of alumina eluted withbenzene. Acidify the eluant with a solution of ethereal hydrogenchloride. The resulting precipitate is suction-filtered, washed withacetone and then with ether and recrystallised from ethanol.

Yield: 72% Melting point: 240°-241° C. (decomposition) Percentagecomposition: Calculated: C 47.8 H 4.6 Br 15.9 Cl 14.1 N 11.2 S 6.4Found: C 47.6 H 4.7 Br 15.8 Cl 14.3 N 11.0 S 6.2 Spectralcharacteristics: Infrared: 1503, 1595, 1615 cm⁻¹ νC=C νC=N

EXAMPLE 302-(5-BROMO-2-THIENYL)-9-(2-MORPHOLINOETHYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE STEP A:2-Amino-3-(5-bromo-2-thenoylmethyl)-1-(2-morpholinoehyl)benzimidazolehydrobromide

Dissolve 2.46 g (10 mmol) of 2-amino-1-(2-morpholinoethyl)benzimidazolein 120 ml of acetone with heating. Subsequently, add5-bromo-2-bromoacethylthiophene. After stirring, leave at roomtemperature for 3 to 4 hours. The2-amino-3-(5-bromo-2-thenoylmethyl)-1-(2-morpholinoethyl)benzimidazolehydrobromide precipitate is filtered, washed twice with 20 ml of acetoneeach time and with ether (20 ml) to obtain 4,7 g of the title compound.

Yield: 88% Melting point: 207°-208° C. Percentage composition:Calculated: C 43.0 H 4.2 Br 30.1 N 10.6 S 6.1 Found: C 43.3 H 4.3 Br30.5 N 10.5 S 5.9 Spectral characteristics:

    ______________________________________                                        Infrared:   1690 cm.sup.-1  ν C═O                                                  1680 cm.sup.-1  ν C═N                                                  3120, 3310 cm.sup.-1                                                                          ν NH.sub.2                                     ______________________________________                                    

STEP B:2-(5-Bromo-2-thienyl)-9-(2-morpholinoethyl)-imidazo(1,2-a]benzimidazole

The hydrobromide obtained in Step A is heated at reflux for 9 hours in50 ml of water in the presence of 2.1 g of sodium hydrogen carbonate.The resulting oil is extracted three times with 15 ml of chloroform eachtime; the organic phases are combined and concentrated by evaporationand then the residue is purified by chromatography on a column ofalumina eluted with chloroform. The first fraction constitutes the titlecompound.

Melting point: 187° C. Percentage composition: Calculated: C 52.9 H 4.4Br 18.5 N 13.0 S 7.4 Found: C 53.0 H 4.5 Br 18.2 N 13.3 S 7.2 Spectralcharacteristics: Infrared: 1500, 1595, 1620 cm⁻¹ νC=C νC=N Spectralcharacteristics: NMR (CDCl₃) δ=2.46 ppm, triplet, 4H, N(CH₂)₂(morpholine) δ=2.76 ppm, triplet, 2H, CH₂ -morpholine δ=3.56 ppm,triplet, 4H, (CH₂)₂ O (morpholine) δ=4.22 ppm, triplet, 2H, CH₂ CH₂-morpholine

STEP C:2-(5-Bromo-2-thienyl)-9-(2-morpholinoethyl)-imidazo[1,2-a]benzimidazoledihydrochloride

The base obtained in the preceding Step is dissolved in acetone (6 mmolper 50 ml) which is acidified with concentrated hydrochloric acid.Thirty minutes later, the resulting precipitate is filtered, and washedwith acetone and with ether.

Yield: 91% Melting point: 237°-238° C. (decomposition) Percentagecomposition: Calculated: C 45.3 H 4.2 Br 15.8 Cl 14.1 N 11.I S 6.4Found: C 45.0 H 4.3 Br 15.4 Cl 14.4 N 11.4 S 6.2

EXAMPLE 312-(2-FURYL)-9-(2-N,N-DIETHYLAMINOETHYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE

The title compound is obtained by proceeding as in Example 30, butreplacing:

1- in Step A

- 2-amino-1-(2-morpholinoethyl)benzimidazole with2-amino-1-(2,N,N-diethylaminoethyl)benzimidazole

- and 5-bromo-2-bromoacetylthiophene with 2-bromoacetylfuran,

2- in Step C

- hydrochloric acid with hydrobromic acid.

Melting point: 269°-270° C. (decomposition) Spectral characteristics: ¹H NMR (CF₃ COOH) δ=1.04 ppm, triplet, 6H, (2CH₃) δ=3.10 ppm, quadruplet,4H, (2CH₂) δ=3.48 ppm, triplet, 2H, CH₂ N(Et)₂ δ=4.90 ppm, triplet, 2H,CH₂ CH₂ N(Et)₂

EXAMPLE 322-(2-FURYL)-9-(2-N,N-DIETHYLAMINOETHYL)-IMIDAZO[1,2-a]BENZIMIDAZOLESULFATE

The title compound is obtained by proceeding as in Example 31 butreplacing hydrobromic acid in Step C with sulfuric acid.

Melting point: 239°-240° C. (decomposition) Percentage composition:Calculated: C 54.3 H 5.7 N 13.3 S 7.6 Found: C 54.3 H 6.0 N 13.5 S 8.0Spectral characteristics: Infrared: 1500, 1595, 1620 cm⁻¹ νC=C νC=N

EXAMPLE 332-(2-FURYL)-9-(2-MORPHOLINOETHYL)-IMIDAZO-[1,2-a]BENZIMIDAZOLEDIHYDROBROMIDE

The title compound is obtained by proceeding as in Example 30 butreplacing the 5-bromo-2-bromoacetylthiophene is Step A with2-bromoacetylfuran and the hydrochloric acid in Step C with hydrobromicacid.

Melting point: 263°-264° C. (decomposition) Percentage composition:Calculated: C 45.6 H 4.5 Br 32.1 N 11.3 Found: C 45.8 H 4.6 Br 31.9 N11.5 Spectral characteristics: Infrared: 1500, 1600, 1630 cm⁻¹ νC=C νC=NSpectral characteristics: ¹ H NMR (CDCl₃) δ=2.48 ppm, triplet, 4H,N(CH₂)₂ morpholine δ=2.79 ppm, triplet, 2H, CH₂ -morpholine δ=3.57 ppm,triplet, 4H, (CH₂)₂ O (morpholine) δ=4.26 ppm, triplet, 2H, CH₂ CH₂morpholine

EXAMPLE 34 9-BENZYL-2-DIETHYLAMINOETHYLIMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE STEP A:9-Benzyl-2-diethylaminoethyl-3-ethoxy-carbonylimidazo[1,2-a]benzimidazole

Add 1.04 ml (10 mmol) of diethylamine to a hot solution of9-benzyl-2-bromoethyl-3-ethoxycarbonylimidazo[1,2-a]benzimidazole (2.01g, 5 mmol), prepared as described for the alkylated analogues in Khim.Farm. ZH 88, 22 (7), 815-9, in 20 ml of benzene. Heat at reflux for onehour, cool. Remove the resulting precipitae, evaporate the benzene, andthe residue is recrystallised by hexane to yield the title compound.

Yield: 96% Melting point: 44°-45° C. Percentage composition: Calculated:C 71.3 H 7.0 N 13.9 Found: C 71.3 H 7.2 N 14.1 Spectral characteristics:

    ______________________________________                                        Infrared:                                                                              1700 cm.sup.-1  ν C═O                                                  1490, 1590, 1605 cm.sup.-1                                                                    ν C═C                                                                            ν C═N                               ______________________________________                                    

STEP B: 9-Benzyl-2-diethylaminomethylimidazo[1,2-a]benzimidazoledihydrochloride

The compound obtained in the preceding Step is dissolved in 35 ml ofconcentrated hydrobromic acid and heated at reflux for 10 hours. Aftercooling, render alkaline using ammonium hydroxide until a pH of 8-9 isreached. Extract with chloroform and pass the residue over a column ofalumina. Elute with chloroform. The oil obtained after evaporation ofthe solvent is dissolved in 20 ml of acetone and the resulting solutionis acidified with ethereal hydrogen chloride. Leave for 2 hours andfilter the resulting precipitate; wash with acetone and purify byreprecipitating with ether an ethanolic solution.

Yield: 61% Melting point: 215°-216° C. (decomposition) Percentagecomposition: Calculated: C 57.1 H 6.9 Cl 16.1 N 12.7 Found: C 57.3 H 7.2Cl 15.7 N 12.5 Spectral characteristics: Infrared: 1620, 1600, 1490 cm⁻¹νC=C νC=N

EXAMPLE 352,9-DIMETHYL-3-(ν-DIMETHYLAMINOPROPOXYCARBONYL)-IMIDAZO[1,2-a]BENZIMIDAOLEDIHYDROBROMIDE STEP A:2,9-Dimethyl-3-trichloroacetylimidazo[1,2-a]benzimidazole

Pour 5.45 g (30 mmol) of freshly distilled trichloroacetyl chloridedropwise into a boiling solution of2,9-dimethylimidazo[1,2-a]benzimidazole(3.7 g; 20 mmol) obtained asdescribed in Khim. Geterotsikl Soedin, 86, (7), 918-925--in 50 ml ofxylene, with vigorous stirring, over a period of 20 to 30 minutes. Themixture is then heated at reflux for wo hours until the product whichhas initially precipitated is completely dissolved. Cool and filter.Concentrate the mother liquors and add petroleum ehter. Combie with theprecipitate obtained earlier and repeat the operation. The combinedprecipitates are treated with an aqueous solution of sodium hydrogencarbonate and then recrystallised from ethyl acetate.

Yield: 76% Melting point: 187°-188° C. (decomposition) Percentagecomposition: Calculated: C 47.2 H 3.0 Cl 32.2 N 12.7 Found: C 47.6 H 3.1Cl 32.0 N 12.9 Spectral characteristics: Infrared: 1653 cm⁻¹ νC=O

STEP B:2,9-Dimethyl-3-(ν-dimethylaminopropoxycarbonyl)-imidazo[1,2-a]benzimidazoledihydrobromide

The sodium alkoxide (obtained from 0.5 g of sodium and 2.5 ml (20 mmol)of ν-dimethylaminopropanol in 40 ml of benzene) is added dropwise to asuspension of 2.31 g (7 mmol) of the trichloroketone obtained in thepreceding Step in 30 ml of benzene. Heat that mixture until the ketonecrystals disappear. Evaporate, treat the residue with 20 ml of water andextract three times with 10 ml of chloroform each time. Concentrate theorganic phases and purify by passing over a coulmn of alumina (eluant:chloroform) to obtain 2 g (yield 91%) of3-(ν-dimethylaminopropoxycarbonyl)-2,9-dimethylimidazo[1,2-a]benzimidazole.The oil so obtained is dissolved in 25 ml of acetone and the solution isacidified with concentrated hydrobromic acid. Collect the precipitateand wash with acetone and with ether.

Melting point: 198° C. Percentage composition: Calculated: C 42.9 H 5.1Br 33.6 N 11.8 Found: C 42.7 H 5.0 Br 32.3 N 11.8 Spectralcharacteristics: Infrared: 1700 cm⁻¹ νC=O

EXAMPLE 363-DIETHYLAMINOMETHYL-2,6,7-TRIMETHYL-9-ETHYLIMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE STEP A:3-Diethylaminomethyl-2,6,7-trimethyl-9-ethyl-imidazo[1,2-a]benzimidazole

A solution of 1.5 g (6.5 mmol) of2,6,7-trimethyl-9-ethylimidazo[1,2-a]benzimidazole in 8 ml of ethanol ismixed with 0.6 ml (7.5 mmol) of 40% formaldehyde and diethylamine (0.76ml, 7.5 mmol). Stir at room temperature. Once the reaction is complete(verified by thin- layer chromatographiy), evaporate, wash the residuewith water, dry, and recrystallise from petroleum ether.

Yield: 93% Melting point: 117° C. Percentage composition: Calculated: C73.0 H 9.0 N 18.0 Found: C 73.2 H 9.0 N 17.9 Spectral characteristics:Infrared: 1500, 1595, 1605 cm⁻¹ νC=C νC=N

STEP B:3-Diethylaminomethyl-2,6,7-trimethyl-9-ethylimidazo-[1,2-a]benzimidazoledihydrochloride

Dissolve 1.86 g (6 mmol) of the base obtained in Step A in 20 ml ofacetone and add concentrated hydrochloric acid. An oil appears which, bymeans of trituration, allows a precipitate to be obtained which ispurified by reprecipitation with ether from an ethanolic solution.

Yield: 92% Melting point: 130°-135° C. (decomposition) Percentagecomposition: Calculated: C 59.2 H 7.9 Cl 18.4 N 14.5 Found: C 59.1 H 8.0Cl 18.2 N 14.6

EXAMPLE 373-DIMETHYLAMINOETHYL-2-PHENYL-9-ETHYLIMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE

The title compound is obtained by proceeding as in Example 36 butreplacing, on the one hand,2,6,7-trimethyl-9-ethylimidazo[1,2-a]benzimidazole by the 9-methylhomologue (obtained by a process identical to that described in KhimGeterotskil. Soedin 86, 7,918-925) and, on the other hand, diethylamineby dimethylamine.

Melting point: 159°-160° C. (decomposition) Percentage composition:Calculated: C 61.4 H 6.2 Cl 18.1 N 14.3 Found: C 61.2 H 6.2 Cl 18.0 N14.2

EXAMPLE 383-PIPERIDINOMETHYL-2-PHENYL-9-ETHYLIMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE

The title compound is obtained by proceeding as in Example 37 butreplacing the dimethylamine with piperidine.

Melting point: 154°-155° C. (decomposition) Percentage composition:Calculated: C 64.0 H 6.6 Cl 16.4 N 13.0 Found: C 64.2 H 6.6 Cl 16.1 N13.3

EXAMPLE 392-METHYL-9-(2-MORPHOLINOETHYL)-3-(4-CHLOROBENZOYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE STEP A:2-Amino-4-(4-chlorophenacyl)-1-(2-morpholinoethyl)benzimidazoliumbromide

A solution of 2.33 g (10 mmol) of 4-chlorophenyl bromide in 25 ml ofacetone is added to a hot solution of2-amino-1-(2-morpholinoethyl)benzimidazole (2.46 g, 10 mmol) in 75 ml ofacetone. The mixture is stirred, heated at the boil for 5 minutes andmaintained at room temperature. Three hours later a precipitate of thetitle compound appears, which is filtered and washed with acetone andwith ether.

Yield: 95% Melting point: 193°-194° C. Percentage composition:Calculated: C 52.6 H 5.0 Br 16.6 Cl 7.4 N 11.7 Found: C 52.5 H 5.1 Br16.2 Cl 7.7 N 11.9 Spectral characteristics:

    ______________________________________                                        Infrared:   1700 cm.sup.-1 ν C═O                                                   1680 cm.sup.-1 ν C═C                                                   3170 cm.sup.-1 ν NH.sub.2                                      ______________________________________                                    

STEP B:2-Methyl-9-(2-morpholinoethyl)-3-(4-chlorobenzoyl)imidazo[1,2-a]benzimidazole

2.4 g of the product obtained in Step A are suspended in 25 ml of aceticanhydride and maintained at room temperature for 24 hours. The reactionmixture is then heated in a bain-marie until the precipitate that hasformed is dissolved, and is then heated at reflux for 10 minutes. Aftercooling, the solution is poured into 100 ml of water and, afterdecomposition of the excess acetic anhydride with ammonium hydroxide,extracted twice with benzene. The combined extracts are concentrated andpassed over a column of alumina (eluant:benzene). The eluant isevaporated to yield the title compound.

Yield: 86% Melting point: 147°-148° C. Percentage composition:Calculated: C 65.3 H 5.5 Cl 8.4 N 13.3 Found: C 65.4 H 5.7 Cl 8.2 N 13.0Spectral characteristics:

    ______________________________________                                        Infrared:                                                                            1500, 1595, 1625 cm.sup.-1                                                                            ν C═C                                                                         ν C═N                                   1640 cm.sup.-1 ν CO                                                 ______________________________________                                    

STEP C:2-Methyl-9-(2-morpholinoethyl)-3-(4-chlorobenzoyl)imidazo[1,2-a]benzimidazoledihydrochloride

1.7 g of the base obtained in Step B is dissolved in 30 ml of acetoneand acidified with concentrated hydrochloric acid: the title compoundprecipitate is removed by filtration and recrystallised from ethanol.

Yield: 89% Melting point: 235°-236° C. Percentage composition:Calculated: C 55.7 H 5.1 Cl 21.5 N 11.3 Found: C 55.4 H 5.1 Cl 21.1 N11.4

EXAMPLE 402-METHYL-9-(2-PIPERIDINOETHYL)-3-(2-FUROYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE

The title compound is obtained by proceeding in the same manner as inExample 39 but replacing the 4-chlorophenacyl bromide in Step A with2-furoylmethyl bromide, and the2-amino-1-(2-morpholinoethyl)benzimidazole with2-amino-1-(2-piperidinoethyl) benzimidazole.

Melting point: 227°-228° C. Percentage composition: Calculated: C 58.8 H5.8 Cl 15.8 N 12.5 Found: C 58.6 H 5.7 Cl 15.5 N 12.7 Spectralcharacteristics:

    ______________________________________                                        Infrared:                                                                            1495, 1600, 1610 cm.sup.-1                                                                            ν C═C                                                                         ν C═N                                   1625 cm.sup.-1 ν CO                                                 ______________________________________                                    

EXAMPLE 412-METHYL-9-(2-PIPERIDINOEHTYL)-3-(2-THENOYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE STEP A:2-Amino-1-(2-piperidinoethyl)-3-(2-thenoylmethyl)benzimidazolium bromide

An ethereal solution of 2-bromoacetylthiophene (obtained by brominating2-acetylthiophene (1.9 g, 15 mmol) with 0.8 ml (15 mmol) of bromine in10 ml of dioxane and 15 ml of ether) is added to a hot solution of2-amino-1-(2-piperidinoethyl)benzimidazole (2.44 g; 10 mmol) in 100 mlof acetone. Stir and maintain at room temperature. The next day, thetitle compound precipitate is collected by means of filtration andwashed with acetone and with ether.

Yield: 94% Melting point: 198° C. (decomposition) Percentagecomposition: Calculated: C 53.3 H 5.6 Br 17.6 N 12.5 S 7.2 Found: C 53.5H 5.6 Br 17.4 N 12.3 S 7.0 Spectral characteristics:

    ______________________________________                                        Infrared:   1685 cm.sup.-1  ν C═O                                                  1675 cm.sup.-1  ν C═N                                                  3210, 3340 cm.sup.-1                                                                          ν NH.sub.2                                     ______________________________________                                    

STEP B:2-Methyl-9-(2-piperidinoehtyl)-3-(2-thenoyl)imidazo[1,2-a]benzimidazole

The bromide obtained in Step A is heated at reflux in 15 ml of aceticanhydide until completely dissolved. Cool and pour into 50 ml of coldwater. Neutralise with a solution of sodium carbonate and extract twicewith 10 ml of chloroform each time. Combine the organic phases, passover a column of alumina and evaporate. Recrystallise the residue fromethyl acetate.

Yield: 92% Melting point: 125°-126° C. (decomposition) Percentagecomposition: Calculated: C 67.5 H 6.2 N 14.3 S 8.2 Found: C 67.6 H 6.4 N14.3 S 8.0 Spectral characteristics:

    ______________________________________                                        Infrared:                                                                            1510, 1590, 1605 cm.sup.-1                                                                            ν C═C                                                                         ν C═N                                   1625 cm.sup.-1 ν CO                                                 ______________________________________                                    

STEP C:2-Methyl-9-(2-piperidinoethyl)-3-(2-thenoyl)-imidazo[1,2-a]benzimidazoledihydrochloride

Dissolve 4 mmol of the compound obtained in the preceding Step in 20 mlof acetone. Acidify with concentrated hydrochloric acid. Filter andrecrystallise from ethanol.

Yield: 87% Melting point: 232° C. (decomposition) Percentagecomposition: Calculated: C 56.8 H 5.6 Cl 15.2 N 12.0 S 6.9 Found: C 56.3H 5.5 Cl 15.6 N 12.2 S 7.0

EXAMPLE 422-METHYL-9-(2-PIPERIDINOETHYL)-3-(2-THENOYL)-IMIDAZO[1,2-a]BENZIMIDAZOLESULFATE

The title compound is obtained by proceeding as in Example 41 butreplacing the hydrochloric acid in Step C with sulfuric acid.

Melting point: 240°-241° C. (decomposition) Percentage composition:Calculated: C 53.9 H 5.3 N 11.4 Found: C 53.8 H 5.3 N 11.3

EXAMPLE 432-METHYL-9-(2-MORPHOLINOETHYL)-3-(5-BROMO-2-THENOYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE

The title compounde is obtained by proceeding as in Example 41 but inStep A replacing

- 2-acetylthiophene with 2-acetyl-5-bromothiophene

- 2-amino-1-(2-piperidinoethyl)benzimidazole with2-amino-1-(2-morpholinoethyl)benzimidazole.

Melting point: 249° C. (decomposition) Percentage composition:Calculated: C 46.2 H 4.2 Br 14.6 Cl 13.0 N 10.3 S 5.9 Found: C 46.5 H4.4 Br 14.4 Cl 13.0 N 10.2 S 6.0 Spectral characteristics:

    ______________________________________                                        Infrared:                                                                            1500, 1600, 1610 cm.sup.-1                                                                            ν C═C                                                                         ν C═N                                   1625 cm.sup.-1 ν CO                                                 ______________________________________                                    

EXAMPLE 44 2-TERT-BUTYL-1-(2-MORPHOLINOETHYL)IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE ##STR37## STEP A:2-(2-Hydroxyethylamino)-1-pivaloylmethyl-benzimidazole hydrobromide

Heat at reflux for 3 hours a mixture of2-(2-hydroxyethylamino)benzimidazole (1.77 g, 10 mmol) andbromopinacoline (1.35 g, 10 mmol) in 50 ml of propanol. Subsequentlymaintain at room temperature. The next day, the title compound iscollected by filtration and washed with acetone and then with ether.

Yield: 89% Melting point: 212°-213° C. (decomposition) Percentagecomposition: Calculated: C 50.6 H 6.2 Br 22.1 N 11.8 Found: C 50.5 H 6.5Br 22.0 N 11.7 Spectral characteristics:

    ______________________________________                                        Infrared: 1720 cm.sup.-1                                                                              ν C═O                                                    3285, 3365 cm.sup.-1                                                                        ν OH    ν NH                                    ______________________________________                                    

STEP B: 2-tert-Butyl-1-(2-hydroxyethyl)imidazo[1,2-a]benzimidazole

The hydrobromide obtained in the preceding Step is placed in areceptacle at 225° C. for 10 minutes. The product obtained is treatedwith ammonium hydroxide and extracted three times with 5 ml ofchloroform each time. The organic phases are combined, concentrated andpassed over a column of alumina eluted with chloroform. The oil obtainedafter evaporation is crystallised by trituration in petroleum ether.

Yield: 70% Melting point: 157°-158° C. Percentage composition:Calculated: C 70.3 H 7.6 N 16.1 Found: C 70.2 H 7.5 N 16.3 Spectralcharacteristics:

    ______________________________________                                        Infrared: 1640 cm.sup.-1 ν C═N                                                   3065, 3205 cm.sup.-1                                                                         ν OH associated                                   ______________________________________                                    

STEP C: 2-tert-Butyl-1-(2-chloroethyl)imidazo[1,2-a]benzimidazolehydrochloride

Add 0.93 ml of thionyl chloride to a suspension of 1.85 g (7.1 mmol) ofthe compound obtained in Step B in 20 ml of chloroform while stirringvigorously. Heat at reflux for two hours and cool. Evaporate andtriturate the residue in petroleum ether. The precipitate obtained iscollected by filtration and washed with petroleum ether.

Yield: 100% Melting point: 200°-201° C. (decomposition) Percentagecomposition: Calculated: C 57.7 H 6.1 Cl 22.7 N 13.5 Found: C 57.9 H 6.0Cl 22.5 N 13.6 Spectral characteristics:

    ______________________________________                                        Infrared:  1520, 1620 cm.sup.-1                                                                          ν C═C                                                  2300, 2800 cm.sup.-1                                                                          ν -N.sup.+ H                                    ______________________________________                                    

STEP D: 2-tert-Butyl-1-(2-morpholinoethyl)-imidazo[1,2-a]benzimidazole

Heat 1 g (3.2 mmol) of the compound obtained in the preceding Step atthe boil for 6 hours in 5 ml of morpholine. Cool, then pour into 10 mlof water. Extract three times with chloroform. Combine the organicphases, wash with water and pass over a column of alumina eluted withchloroform. Evaporate the solvent. The title compound is obtained.

Yield: 89% Percentage composition: Calculated: C 69.9 H 8.0 N 17.2Found: C 70.0 H 7.8 N 17.4 Spectral characteristics: ¹ H NMR δ=1.41 ppm,singlet, 9H, C(CH₃)₃ δ=1.50 ppm, triplet, 4H, (CH₂)₂ N δ=2.86 ppm,triplet, 2H, CH₂ -morpholine δ=3.63 ppm, triplet, 4H, (CH₂)₂ O δ=4.28ppm, triplet, 2H, CH₂ CH₂ -morpholine

STEP E: 2-tert-butyl-1-(2-morpholinoethyl)-imidazo[1,2-a]benzimidazoledihydrochloride

The oil obtained in Step D is dissolved in 15 ml of acetone and thesolution obtained is acidified with ethereal hydrogen chloride. Filterthe precipitate obtained. Wash with acetone and dry.

Yield: 85% Melting point: 288° C. (decomposition) Percentagecomposition: Calculated: C 57.1 H 7.1 Cl 17.8 N 14.0 Found: C 57.3 H 7.2Cl 17.5 N 13.8 Spectral characteristics: Infrared: 1665 cm⁻¹ νC=N⁺2200-2700, 3300-3450 cm⁻¹ νNH⁺

EXAMPLE 452-TERT-BUTYL-1-(2-PIPERIDINOETHYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE

The title compound is obtained by proceeding as in Example 44 butreplacing the morpholine in Step D with piperidine.

Melting point: 231° C. (decomposition) Percentage composition:Calculated: C 60.4 H 7.6 Cl 17.8 N 14.1 Found: C 60.6 H 7.9 Cl 17.5 N14.0 Spectral characteristics: Infrared: 1660 cm⁻¹ νC=N⁺ 2200-2700,3300-3450 cm⁻¹ νNH⁺

EXAMPLE 462-TERT-BUTYL-1-(2-N,N-DIMETHYLAMINOETHYL)-IMIDAZO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE

The title compound is obtained by proceeding as in Example 44 butreplacing the morpholine in Step D with N,N-diethylamine.

Melting point (hydrate): 240°-241° C. (decomposition) Percentagecomposition: Calculated: C 56.6 H 8.0 Cl 17.6 N 13.9 Found: C 56.6 H 7.8Cl 17.3 N 14.0 Spectral characteristics: ¹ H NMR (CDCl₃) base δ=0.72ppm, triplet, 6H, 2CH₃ δ=1.41 ppm, singlet, 9H, C(CH₃)₃ δ=2.35 ppm,quadruplet, 4H, N(CH₂)₂ δ=2.76 ppm, triplet, 2H, CH₂ --N(Et)₂ δ=4.18ppm, triplet, 2H, CH₂ --CH₂ --N(Et)₂ δ=6.9 ppm, singlet, 1H, imidazoleδ=7.12-7.45 ppm, unresolved peaks, 4H, aromatic

EXAMPLE 47 10-(2-DIETHYLAMINOETHYL)-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLE DIHYDROCHLORIDE ##STR38## STEP A:10-(2-Diethylaminoethyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole

Heat at reflux for five hours a mixture of 2.32 g (10 mmol) of2-amino-1-diethylaminoethyl benzimidazole and 1.2 ml (10 mmol) of1-bromo-3-chloropropane in 10 ml of xylene. Add 50 ml of water and stiruntil a solution is obtained. Separate the aqueous phase, renderalkaline with ammonium hydroxide to a pH of 9, and extract three timeswith chloroform. Combine the organic phases, concentrate and elute withchloroform on a column of alumina. Collect the first fraction andevaporate the solvent. Dry.

Yield: 86% Percentage composition: Calculated: C 66.2 H 9.0 N 19.3Found: C 66.0 H 9.3 N 19.5 Spectral characteristics: Infrared: 1660 cm⁻¹νC=N

STEP B:10-(2-diethylaminoethyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazoledihydrochloride (dihydrate)

The base obtained in the preceding Step is dissolved in 20 ml of etherand the solution is acidified with ethereal hydrogen chloride. Filterthe precipitate obained, wash with ether and dry.

Yield: 91.6% Melting Point: 78°-80° C. (decomposition) Percentagecomposition (dihydrate): Calculated: C 50.4 H 7.9 Cl 18.6 N 14.7 Found:C 50.1 H 8.2 Cl 18.4 N 14.5

EXAMPLE 48 10-PHENACYL-2,3,4,10-TETRAHYDROPYRIDINO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE STEP A: 2-(3-Hydroxypropylamino)benzimidazole

Heat at 145°-150° C. for two hours a mixture of 5 g (25 mmol) of2-benzimidazolesulfonic acid and 5.7 ml (75 mmol) of 3-aminopropanol.Cool to 90° C. and add 15 ml of cold water, with vigorous stirring,until a precipitate is formed. Maintain at a temperature ofapproximately 4° C. for one night, filter the title compoundprecipitate, wash with cold water and dry.

Yield: 95% Melting Point: 139°-140° C. Percentage composition(dihydrate): Calculated: C 62.8 H 6.9 N 22.0 Found: C 62.6 H 6.9 N 22.3Spectral characteristics:

    ______________________________________                                        Infrared:                                                                              1500, 1580, 1600 cm.sup.-1                                                                     ν C═C                                                 1650 cm.sup.-1   ν C═N                                                 3070-3240 cm.sup.-1                                                                            ν OH  ν NH                                    ______________________________________                                    

STEP B: 2-(3-Hydroxypropylamino)-1-phenacylbenzimidazole hydrobromide

Heat at reflux for 5 to 6 hours a mixture of 1.91 g (10 mmol) of thecompound obtained in Step A and 1.99 g (10 mmol) of phenacyl bromide in20 ml of isopropanol. Cool. Collect the title compound precipitate byfiltration and wash with acetone. Recrystallise from ethanol.

Yield: 82% Melting Point: 237°-238° C. Percentage composition:Calculated: C 55.4 H 5.2 Br 20.5 N 10.8 Found: C 55.6 H 5.1 Br 20.0 N10.5 Spectral characteristics:

    ______________________________________                                        Infrared:                                                                              1700 cm.sup.-1                                                                              ν CO                                                         1650 cm.sup.-1                                                                              ν C═N                                                    3100-3240 cm.sup.-1                                                                         ν OH    ν NH                                     ______________________________________                                    

STEP C: 10-Phenacyl-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole

With stirring, slowly add 0.7 ml (10 mmol) of thionyl chloride to asuspension of 1.95 g (5 mmol) of the compound obtained in Step B in 25ml of chloroform. Heat at reflux until the starting material and itschlorinated derivative have disappeared (monitored by thin-layerchromatography). Evaporate the reaction mixture, treat the residue withammonium hydroxide and extract three times with chloroform. Combine theorganic phases, evaporate, and heat the residue at 110°-120° C. for 20minutes; treat with ammonium hydroxide and with chloroform.

The chloroform phase is passed over a column of alumina eluted withchloroform. Collect the fraction R_(f) ˜0.3. Evaporate the solvent andrecrystallise the title compound from acetonitrile.

Yield: 86.2% Melting point: 168°-169° C. (decomposition) Percentagecomposition: Calculated: C 74.2 H 5.9 N 14.4 Found: C 74.2 H 5.7 N 14.2Spectral characteristics:

    ______________________________________                                        Infrared: 1505, 1590, 1605 cm.sup.-1                                                                       ν C═C                                               1660 cm.sup.-1     ν C═N                                               1690 cm.sup.-1     ν C═O                                     ______________________________________                                    

¹ H NMR (CDCl₃): base δ=1.89 ppm, unresolved peaks, 2H, CH₂ (3) δ=3.45ppm, triplet, 2H, N--CH₂ (4) δ=3.75 ppm, triplet, 2H, N--CH₂ (2) δ=5.10ppm, singlet, 2H, CH₂ --CO δ=6.80 ppm, unresolved peaks, 9H, aromatic

STEP D: 10-Phenacyl-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazolehydrochloride

The compound obtained in Step C is dissolved in acetone. The solutionobtained is treated with concentrated hydrochloric acid. Suction-filterthe precipitate and recrystallise from ethanol.

Melting point: 288°-289° C. Percentage composition: Calculated: C 66.0 H5.5 Cl 10.8 N 12.8 Found: C 65.7 H 5.7 Cl 11.0 N 12.5 Spectralcharacteristics:

    ______________________________________                                        Infrared: 1670 cm.sup.-1                                                                              ν (C═N.sup.+ -H)                                         1700 cm.sup.-1                                                                              ν (C═O)                                        ______________________________________                                    

EXAMPLE 49 10-PHENACYL-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLESTEP A: [1H]-1,2,3,4-tetrahydropyrimidino[1,2-a]benzimidazole

Add a solution of thionyl chloride in dimethylformamide dropwise, atroom temperature, to a solution obtained by heating2-(3-hydroxypropylamino)benzimidazole (obtained in Example 48, Step A)in dimethylformamide. Subsequently, heat at reflux for four hours, cool,dilute with water and neutralise with ammonium hydroxide. Thirty minuteslater, separate the title compound, wash with water and recrystallisefrom acetonitrile.

Yield: 82% Melting point: 210°-211° C. Percentage composition:Calculated: C 69.4 H 6.5 N 24.1 Found: C 69.3 H 6.4 N 24.3 Spectralcharacteristics: Infrared: 1620 cm⁻¹ νCN ¹ H NMR (CDCl₃): δ=2.12 ppm,triplet, 2H, CH₂ (3) δ=3.47 ppm, triplet, 2H, CH₂ (4) δ=3.91 ppm,triplet, 2H, CH₂ (2) δ=6.95-7.20 ppm, 5H, aromatic

STEP B: 10-Phenacyl-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole

1.38 g (8 mmol) of the compound obtained in Step A is dissolved in 50 mlof xylene at 120° C. Cool to 50° C. and add 1.59 g (8 mmol) of phenacylbromide. Stir vigorously until dissolved, then heat at the boil andleave at reflux for one hour. Cool, separate the precipitate formed,wash with petroleum ether, dry and treat with ammonium hydroxide.Separate the title compound precipitate and recrystallise fromacetonitrile.

Yield: 95% Melting point: 168°-169° C. (decomposition)

EXAMPLE 5010-(4'-CHLOROPHENACYL)-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE

The title compound is obtained by proceeding as in Examples 48 and 49but replacing the phenacyl bromide in Steps B with 4-chlorophenacylbromide.

Melting point: 270°-271° C. Percentage composition: Calculated: C 59.7 H4.7 Cl 19.6 N 11.6 Found: C 59.5 H 4.5 Cl 19.3 N 11.5 Spectralcharacteristics:

    ______________________________________                                        Infrared:   1670 cm.sup.-1                                                                              ν C═N.sup.+                                              1700 cm.sup.-1                                                                              ν C═O                                        ______________________________________                                    

¹ H NMR (CDCl₃): δ=1.89 ppm, unresolved peaks, 2H, CH₂ (3) δ=3.45 ppm,unresolved peaks, 2H, CH₂ (4) δ=3.75 ppm, unresolved peaks, 2H, CH₂ (2)δ=5.20 ppm, singlet, 2H, CH₂ --CO

EXAMPLE 5110-(4'-METHOXYPHENACYL)-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE

The title compound is obtained by proceeding as in Steps B with4-methoxyphenacyl bromide.

Melting point: 260°-262° C. (decomposition) Percentage composition:Calculated: C 63.8 H 5.6 Cl 9.9 N 11.7 Found: C 63.9 H 5.5 Cl 10.1 N11.5 Spectral characteristics:

    ______________________________________                                        Infrared:  1670 cm.sup.-1                                                                              ν C═N.sup.+ H                                            1690 cm.sup.-1                                                                              ν CO                                              ______________________________________                                    

δ=1.89 ppm, quintuplet, 2H, CH₂ (3) δ=3.48 ppm, triplet, 2H, CH₂ (4)δ=3.25 ppm, triplet, 2H, CH₂ (2) δ=3.78 ppm, singlet, 3H, OCH₃ δ=5.10ppm, singlet, 2H, CH₂ --CO

EXAMPLE 5210-[2-HYDROXY-2-(4-CHLOROPHENYL)ETHYL]-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE STEP A:10-[2-Hydroxy-2-(4-chlorophenyl)ethyl]-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole

Add 0.35 g (9.3 mmol) of sodium borohydride in small portions, withvigorous stirring, to a suspension of 3.0 g (9.3 mmol) of10-(4-chlorophenacyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole(obtained in Example 50) in 20 ml of ethanol. Maintain stirring for onehour and leave for 12 hours at room temperature. Acidify withhydrochloric acid, and evaporate the reaction mixture. Treat the residuewith ammonium hydroxide and extract with chloroform. The organic phaseobtained is passed over a column of alumina. Evaporate the solvent. Theresidue is the title compound.

Melting point: 146°-147° C. Percentage composition: Calculated: C 65.9 H5.5 Cl 10.8 N 12.8 Found: C 65.6 H 5.7 Cl 10.5 N 12.5 Spectralcharacteristics:

    ______________________________________                                        Infrared:  1490, 1600 cm.sup.-1                                                                           ν C═C                                                 1650 cm.sup.-1   ν C═N                                      ______________________________________                                    

¹ H NMR (CDCl₃): δ=1.91 ppm, quintet, 2H, CH₂ (3) δ=3.51 ppm, triplet,2H, CH₂ (4) δ=3.74 ppm, triplet, 2H, CH₂ (2) δ=3.94 ppm, triplet, 1H, CHδ=5.00 ppm, doublet, 2H, CH₂ --CH

STEP B:10-[2-Hydroxy-2-(4-chlorophenyl)ethyl]-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazolehydrochloride

Slowly add isopropanolic hydrogen chloride to an isopropanol solution ofthe base obtained in Step A. Wait for 30 minutes. Suction-filter, andwash with acetone.

Yield: 90% Melting point: 253°-254° C. (decomposition) Percentagecomposition: Calculated: C 59.3 H 5.3 Cl 19.5 N 11.5 Found: C 59.4 H 5.5Cl 19.4 N 11.3

EXAMPLE 5310-[2-HYDROXY-2-(4-METHOXYPHENYL)ETHYL]-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE

The title compound is obtained by proceeding as in Example 52 butreplacing the10-(4-chlorophenacyl)-2,3,4,10-tetrahydro-pyrimidino[1,2-a]benzimidazolein Step A with10-(4-methoxyphenacyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazoleobtained in Example 51.

Melting point: 210°-212° C. Percentage composition: Calculated: C 63.4 H6.2 Cl 9.9 N 11.7 Found: C 63.2 H 6.5 C19.5 N 11.9 Spectralcharacteristics:

    ______________________________________                                        Infrared:  1500-1610 cm.sup.-1                                                                            ν C═C                                                 1640 cm.sup.-1   ν C═N                                      ______________________________________                                    

¹ H NMR (CDCl₃): δ=1.85 ppm, quadruplet, 2H, CH₂ (3) δ=3.87 ppm,triplet, 1H, CH δ=4.92 ppm, doublet, 2H, CH₂ CH

EXAMPLE 541-(2-DIETHYLAMINOETHYL)-1,2,3,4-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLESULFATE (TRIHYDRATE) ##STR39## STEP A:1-(2-Diethylaminoethyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

Heat at reflux for 12 hours a mixture of 1.16 g (5 mmol) of2-(2-diethylaminoethylamino) benzimidazole and 0.6 ml (5 mmol) of1-bromo-3-chloropropane in 10 ml of xylene. After cooling, the xylene isdecanted off and the residual oil is treated with petroleum ether.Evaporate the remaining petroleum ether and treat with ammoniumhydroxide. Extract with chloroform. The combined organic phases areconcentrated and passed over a column of alumina eluted with chloroform.The evaporation of the solvent allows the title compound to be obtained.

Yield: 42% Percentage composition: Calculated: C 70.5 H 8.9 N 20.6Found: C 70.4 H 9.1 N 20.8 Spectral characteristics: Infrared: 1625 cm⁻¹ν(C=N) ¹ H NMR (CDCl₃): δ=0.97 ppm, triplet, 6H, (2CH₃) δ=2.16 ppm,quintuplet, 2H, CH₂ (3) δ=2.55 ppm, quadruplet, 4H, N(CH₂)₂ δ=2.72 ppm,triplet, 2H, CH₂ N δ=3.47 ppm, triplet, 2H, CH₂ (4) δ=3.66 ppm, triplet,2H, CH₂ (2) δ=3.89 ppm, triplet, 2H, NCH₂ CH₂ N(Et)₂

STEP B:1-(2-Diethylaminoethyl)-1,2,3,4-tetrahydropyrimidino[1,2-a]benzimidazolesulfate (trihydrate)

Dissolve the base obtained in Step A in 10 ml of acetone and acidifywith sulfuric acetone. Triturate and add acetone in small portions;filter; dry and recrystallise from acetonitrile.

Yield: 98% Percentage composition (trihydrate): Calculated: C 45.5 H 7.6N 13.3 S 7.6 Found: C 45.5 H 7.5 N 13.0 S 7.4

EXAMPLE 551-(2-PIPERIDINOETHYL)-1,2,3,4-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE (TRIHYDRATE)

The title compound is obtained by proceeding as in Example 54 butreplacing the 2-(2-diethylaminoethylamino)benzimidazole in Step A with2-(2-piperidinoethylamino) benzimidazole and the sulfuric acid in Step Bwith hydrochloric acid.

Melting point: 188°-190° C. (decomposition) Percentage composition:Calculated: C 49.6 H 7.8 Cl 17.2 N 13.6 Found: C 49.6 H 7.9 Cl 16.9 N13.5 Spectral characteristics: Infrared: 1620 cm⁻¹ νC=N ¹ H NMR (CDCl₃):δ=1.44 ppm, unresolved peaks, 6H, piperidine δ=2.15 ppm, quintuplet, 2H,CH₂ (3) δ=2.42 ppm, unresolved peaks, 4H, piperidine δ=2.63 ppm,triplet, 2H, CH₂ --N δ=3.43 ppm, triplet, 2H, CH₂ (4) δ=3.68 ppm,triplet, 2H, CH₂ (2)

EXAMPLE 561-(2-MORPHOLINOETHYL)-1,2,3,4-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLEDIHYDROCHLORIDE (TRIHYDRATE) ##STR40##

The title compound is obtained by proceeding as in Example 55 butreplacing the 2-(2-piperidinoethylamino)benzimidazole with2-(2-morpholinoethylamino)benzimidazole.

Melting point: 284°-285° C. (decomposition) Percentage composition:Calculated: C 48.6 H 7.1 Cl 17.9 N 14.2 Found: C 48.4 H 7.0 Cl 18.0 N14.2 Spectral characteristics: Infrared: 1620 cm⁻¹ νC=N ¹ H NMR (CDCl₃):δ=2.16 ppm, quintuplet, 2H, CH₂ (3) δ=2.46 ppm, multiplet, 4H,morpholine N CH₂ (2) δ=2.63 ppm, triplet, 2H, CH₂ -morpholine δ=3.43ppm, triplet, 2H, CH₂ (4) δ=3.65 ppm, unresolved peaks, 6H, morpholineand CH₂ (2) δ=3.88 ppm, triplet, 2H, CH₂ --CH₂ -morpholine

EXAMPLE 579-[2-HYDROXY-2-(4-METHOXYPHENYL)ETHYL]-2,3-DIHYDROIMIDAZO[1,2-a]BENZIMIDAZOLEHYDROCHLORIDE

Add 0.3 g (7.5 mmol) of sodium borohydride bit by bit to a suspension of2.41 g (7 mmol) of9-(4'-methoxyphenacyl)-2,3-dihydroimidazo[1,2-a]benzimidazole--describedin Example 6--in 15 ml of methanol over a period of thirty minutes atroom temperature. Continue stirring for a further four hours and leaveuntil the next day. Subsequently, add 10 ml of 10% hydrochloric aciduntil a pH of 2-3 is obtained, and evaporate the methanol. Treat theresidue with an ammonium hydroxide solution and extract with chloroform.Recrystallise the residue. The title compound is obtained in the form ofa base. Dissolve in hot ethanol and add ethereal hydrogen chloride.Allow to cool, suction-filter, and wash with ether. The title compoundis obtained.

Melting point: 192°-193° C. Percentage composition: Calculated: C 62.5 H5.8 Cl 10.3 N 12.1 Found: C 62.6 H 6.0 Cl 10.5 N 12.4 Spectralcharacteristics: Infrared: 1660 cm⁻¹ ν(C=N) 3100-3600 cm⁻¹ ν(OH) Nuclearmagnetic resonance: (¹ H) (CF₃ COOD) δ=3.5 ppm, singlet, 3H, OCH₃ δ=4.9ppm, triplet, 2H, CH₂

Using the same procedures, the following compounds are obtained:

EXAMPLE 5810-(3',5'-DITERTBUTYL-4'-HYDROXYPHENACYL)-2,3,4,10TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 283°-284° C. (sublimation)

EXAMPLE 599-(3',5'-DITERTBUTYL-4'-HYDROXYPHENACYL)IMIDAZO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 267°-268° C. (sublimation)

EXAMPLE 6010-(3',4'-DIHYDROXYPHENACYL)-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 262°-263° C. (sublimation)

EXAMPLE 61 9-(3',4'-DIHYDROXYPHENACYL)IMIDAZO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 268°-269° C. (sublimation)

EXAMPLE 6210-(4'-HYDROXYPHENACYL)-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 294°-295° C. (sublimation)

EXAMPLE 63 9-(4'-HYDROXYPHENACYL)IMIDAZO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 297°-298° C. (sublimation)

EXAMPLE 6410-(3',4'-DIMETHOXYPHENACYL)-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 263°-264° C. (sublimation)

EXAMPLE 65 9-(3',4'-DIMETHOXYPHENACYL)IMIDAZO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 253°-254° C. (sublimation)

EXAMPLE 6610-(5'-BROMO-2-THENOYLMETHYL)-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 260°-261° C. (sublimation)

EXAMPLE 67 9-(5'-BROMO-2-THENOYLMETHYL)IMIDAZO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 259°-260° C. (sublimation)

EXAMPLE 6810-(2-THENOYLMETHYL)-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 290°-291° C. (sublimation)

EXAMPLE 69 9-(2-THENOYLMETHYL)IMIDAZO[1,2-a]BENZIMIDAZOLE, HYDROBROMIDE

Melting point: 235°-236° C. (sublimation)

EXAMPLE 7010-(3',4'-DICHLOROPHENACYL)-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 278°-279° C. (sublimation)

EXAMPLE 7110-(4'-CHLOROPHENACYL)-2,3,4,10-TETRAHYDROPYRIMIDINO[1,2-a]BENZIMIDAZOLE,HYDROBROMIDE

Melting point: 269°-270° C. (sublimation)

PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION EXAMPLE A ACUTETOXICITY STUDY

The acute toxicity was evaluated after the oral administration togroups, each comprising 8 mice (26±2 grams), of increasing doses of thecompounds being studied. The animals were observed at regular intervalsduring the course of the first day, and daily for two weeks, followingthe treatment. The compounds of the invention appear to be of very lowtoxicity.

EXAMPLE B HYPOGLYCAEMIC ACTIVITY STUDY

The hypoglycaemic activity of the compounds of the invention wasresearched on white rats (160-190 g) using five animals per compoundstudied; the animals are given a diet of water for eighteen hours beforethe beginning of the experiment. The compounds to be studied areadministered by the intraperitoneal route in a single dose of 50mg/kg⁻¹. The blood glucose concentration is determined by samples takenbefore injection of the compound and then 2 hours, 4 hours and 6 hoursafter administration. The dosage was calculated by the fermentationmethod using Bio-La-test kits (Lachema--Czhekoslovakia). Aspectrophotometer KFK-2 (λ=490 nm) was used for that operation.

The blood glucose concentrations were compared with a standard solutionof glucose (10 mmol/l). The compounds of the invention appear to have ahypoglycaemic activity comparable to that of gliclazide. Their durationof action is longer than twelve hours.

EXAMPLE C PLATELET ANTI-AGGREGATION ACTIVITY STUDY

The platelet anti-aggregation activity study of the compounds of theinvention was researched in accordance with the method of G.V.R. BORN(Aggregation of blood platelets by adenosine diphosphate and itsreversal--Nature 1962-v. 194 p 927-929). For those experiments, a rabbitplasma rich in platelets containing at least 2.5×10⁸ platelets per mlwas used. ADP (adenosine diphosphate) acts as an inductor. Before usingADP, the compounds of the invention are placed in the presence of theplatelet-rich plasma. Each compound was studied on five differentspecimens of platelet-rich plasma. The platelet aggregation wasevaluated as a percentage decrease in the optical density of theplatelet-rich plasma by photoelectrocolorimetric recording. The ID₅₀ ofthe compounds of the invention (dose at which platelet aggregation isdecreased by half) is less than 10⁻⁴ M for the compounds of theinvention.

EXAMPLE D ANTIHYPERTENSIVE ACTIVITY RESEARCH

The animals are acclimatised for a period of six days before thebeginning of the study. At the beginning of the experiment, the rats areanaesthetised with 1000 mg/kg⁻¹ of urethane administered by theintraperitoneal route. A catheter is introduced into the jugular vein. Acatheter connected to a precision recorder is placed in the carotidartery. A period of 10 minutes is allowed to pass to allow the arterialpressure to stabilise before taking the first measurement.

In a first period, the solvent is administered by the intravenous routeto all the animals, the arterial pressure is recorded for a period of 30minutes after the administration, and readings of the arterial pressureare taken 10, 20 and 30 minutes after the administration. The compoundsof the invention are administered in saline solution also by theintravenous route. The recording of the arterial pressure is carried outfor a period of 30 minutes and pressure readings are taken 10, 20 and 30minutes after the administration. The compounds of the invention do notbring about any significant decrease in arterial pressure.

EXAMPLE E PHARMACEUTICAL COMPOSITION

Tablets designed for the treatment of diabetes and its complicationscomprising 20 mg of9-(2-diethylaminoethyl)-2,3-dihydroimidazo[1,2-a]benzimidazoledihydrochloride.

    ______________________________________                                        Formulation for 1000 tablets:                                                 ______________________________________                                        9-(2-diethylaminoethyl)-2,3-dihydroimidazo-                                                            20 g                                                 [1,2-a]benzimidazole dihydrochloride                                          wheat starch             15 g                                                 lactose                  65 g                                                 magnesium stearate        2 g                                                 silica                    1 g                                                 hydroxypropylcellulose    2 g                                                 ______________________________________                                    

We claim:
 1. A compound selected from the group consistingof:10-(3',5'-ditertbutyl-4'-hydroxyphenacyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole,9-(3',5'-ditertbutyl-4'-hydroxyphenacyl)imidazo[1,2-a]benzimidazole,10-(3',4'-dihydroxyphenacyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole,9-(3',4'-dihydroxyphenacyl)imidazo[1,2-a]benzimidazole,10-(4'-hydroxyphenacyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole,9-(4'-hydroxyphenacyl)imidazo[1,2-a]benzimidazole,10-(3',4'-dimethoxyphenacyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole,9-(3',4'-dimethoxyphenacyl)imidazo[1,2-a]benzimidazole,10-(5'-bromo-2-thenoylmethyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole,9-(5'-bromo-2-thenoylmethyl)imidazo[1,2-a]benzimidazole,10-(2-thenoylmethyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole,9-(2-thenoylmethyl)imidazo[1,2-a]benzimidazole,10-(3',4'-dichlorophenacyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole,9-(4'-chlorophenacyl)-2,3,4,10-tetrahydropyrimidino[1,2-a]benzimidazole,stereoisomersthereof and addition salts thereof with a pharmaceutically-acceptableacid.
 2. A method for treating an animal or living human body afflictedwith diabetes and/or its cardiovascular complications comprising thestep of administering to the living body an amount of a compound claim 1which is effective for alleviation of said condition.
 3. Apharmaceutical composition useful in the treatment of diabetescomprising as active principle an effective amount of a compound ofclaim 1, together with one or more pharmaceutically-acceptableexcipients or vehicles.
 4. A compound of claim 1 in the form of itshydrobromide.
 5. A method of claim 2 wherein the compound is in the formof its hydrobromide.
 6. A pharmaceutical composition of claim 3 whereinthe compound is in the form of its hydrobromide.